Clinical trial NCT05424549
Conditions: Dry Eye Syndromes
Keywords: dry eye disease reproxalap Aldeyra ADX-102
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2022-03-09; Completion date: 2022-05-09
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A Randomized, Double-Masked, Vehicle-Controlled Crossover Clinical Trial to Assess Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in Subjects with Dry Eye Disease

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) intervention 2: Vehicle Ophthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) dosed six times over two consecutive days intervention 2: Vehicle Ophthalmic Solution dosed six times over two consecutive days

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
A Randomized, Double-Masked, Vehicle-Controlled Crossover Clinical Trial to Assess 
Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in 
Subjects with Dry Eye Disease 
 
Study Sponsor 
Aldeyra Therapeutics, Inc. 
131 Hartwell Avenue, Suite 320 
Lexington, MA 02421, U.S.A. 
Study Number(s) 
ADX-102-DED-027 
 
Study Product(s)  
Product A (Investigational Product): 0.25% Reproxalap Ophthalmic Solution 
(Manufactured by Aldeyra Therapeutics, Inc.) 
Product B (Vehicle): Vehicle Ophthalmic Solution 
(Manufactured by Aldeyra Therapeutics, Inc.) 
Clinical Research 
Organization 
 
  
 
Indication 
Dry Eye Disease (DED) 
Clinical Trial Phase 
Phase 2b 
Regulatory Agency 
Health Canada 
Protocol Version  
3.0  
Protocol Date 
13 Jun 2022 
 
 


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PROTOCOL VERSION CONTROL  
 
Version Number 
Notes/Summary of Changes 
Date 
1.0 
Protocol created  
 
2.0 
Protocol amendment 
 
3.0 
Protocol amendment 
13 Jun 2022 
 
 
 
) 
 
  
 
 
 
 
  
  
 
 
  
 
 
  
  
 
 
  
  
  
  


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SPONSOR APPROVAL / SIGNATURE PAGE 
 
Study Title: A Randomized, Double-Masked, Vehicle-Controlled Crossover Clinical Trial to 
Assess Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in 
Subjects with Dry Eye Disease 
 
 
I, on behalf of Aldeyra Therapeutics, Inc., approve the protocol and agree to conduct this clinical 
trial as outlined in the approved protocol and in accordance with the appropriate guidelines and 
all applicable federal government codes, acts and regulations, the ethical pricinples that have 
their origins in the Declaration of Helsinki and all amendments, Good Clinical Practice (GCP) 
requirements, The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidance E6 (R2) on Good Clinical Practice, and Tri-
Council Policy Statement (Canada). 
 
 
 
 
Sponsor Representative 
                                                  
 
 
 
 


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PRINCIPAL INVESTIGATOR APPROVAL / SIGNATURE PAGE 
 
Study Title: A Randomized, Double-Masked, Vehicle-Controlled Crossover Clinical Trial to 
Assess Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in 
Subjects with Dry Eye Disease 
 
I agree to conduct this clinical trial as outlined in the approved protocol and accordance with all 
applicable federal government codes, acts and regulations, the ethical principles that have their 
origins in the Declaration of Helsinki and all amendments, Good Clinical Practice (GCP) 
requirements, the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidance E6 (R2), and Tri-Council Policy Statement 
(Canada) and to allow applicable regulatory agencies the opportunity to inspect study facilities 
and pertinent records at reasonable times and in a reasonable manner that ensures subject 
confidentiality. 
 
 
Principal Investigator 
  
  
  
 
  
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 9 
1. 
LIST OF ABBREVIATIONS ..............................................................................................13 
2. 
PRINCIPAL INVESTIGATOR ...........................................................................................14 
3. 
SPONSOR REPRESENTATIVE .......................................................................................14 
4. 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................14 
4.1. 
Clinical Research Organization ..................................................................................14 
4.2. 
Clinical Facilities ........................................................................................................14 
4.3. 
Institutional Review Board (IRB) ................................................................................14 
4.4. 
Safety Management...................................................................................................14 
4.5 
Medical Monitor .........................................................................................................15 
5. 
STUDY SUMMARY ...........................................................................................................16 
6. 
STUDY SCHEMATIC ........................................................................................................22 
7. 
INTRODUCTION ...............................................................................................................25 
7.1. 
Background and Study Rationale...............................................................................25 
7.2. 
Nonclinical Data .........................................................................................................26 
7.3. 
Effects in Humans .....................................................................................................26 
7.4. 
Benefit/Risk Assessment ...........................................................................................26 
7.5. 
Rationale for Dose Selection .....................................................................................27 
8. 
OBJECTIVES AND ENDPOINTS .....................................................................................27 
8.1. 
Objectives ..................................................................................................................27 
8.2. 
Endpoints ..................................................................................................................27 
8.2.1. 
Primary Endpoints ..............................................................................................27 
8.2.2. 
Secondary Endpoints .........................................................................................27 
8.2.3 
Safety Endpoints ................................................................................................27 
9. 
STUDY DESIGN ...............................................................................................................28 
9.1. 
Overall Study Design .................................................................................................28 
9.1.1. 
Dry Eye Chamber ..............................................................................................29 
 
 
10. SUBJECT SELECTION ....................................................................................................29 
10.1. 
Number of Subjects ...................................................................................................29 
10.2. 
Inclusion Criteria for Study Volunteers .......................................................................29 


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10.3. 
Exclusion and Restriction Criteria for Study Volunteers .............................................30 
10.3.1. 
Exclusion Criteria ...............................................................................................30 
10.3.2. 
Restrictions and Concomitant Medications.........................................................31 
10.3.3. 
Female Subjects of Childbearing Potential .........................................................32 
10.3.4. 
Male Subjects ....................................................................................................32 
11. STUDY PRODUCT AND TREATMENT SEQUENCE .......................................................33 
11.1. 
Study Product and Treatment ....................................................................................33 
11.2. 
Treatment Sequence .................................................................................................33 
11.3. 
Masking and Unmasking ...........................................................................................33 
11.3.1. 
Masking .............................................................................................................33 
11.3.2. 
Emergency Unmasking ......................................................................................33 
12. STUDY VISITS ..................................................................................................................34 
12.1. 
COVID-19 Screening .................................................................................................34 
12.2. 
Visit 1a: Medical Screening (Day -21 to -8) ................................................................34 
12.3. 
Visit 1b: DEC Screening (Day -14 to -7).....................................................................35 
12.4. 
Visits 2 – Randomization and Baseline Treatment Visit .............................................35 
12.5. 
Visits 3 – DEC Treatment Visit ...................................................................................36 
12.6. 
Visit 4 - Baseline Treatment Visit ...............................................................................37 
12.7. 
Visit 5 – DEC Treatment Visit ....................................................................................37 
12.8. 
Follow-up Phone call follow-up ..................................................................................37 
13. STUDY ASSESSMENTS AND PROCEDURES ................................................................37 
13.1. 
Efficacy Assessments ................................................................................................37 
13.1.1. 
Staff Assessed Ocular Redness .........................................................................37 
13.1.2. 
Unanesthetized Schirmer’s Test ........................................................................38 
13.1.3. 
Visual Analog Scale (VAS) Ocular Dryness .......................................................38 
13.1.4. 
Ocular Itching score ...........................................................................................38 
13.1.5. 
VAS Ocular Discomfort ......................................................................................38 
13.1.6. 
VAS Ocular Burning ...........................................................................................38 
13.1.7. 
VAS Ocular Grittiness ........................................................................................38 
13.1.8. 
VAS Ocular Stinging ..........................................................................................38 
13.2. 
Safety Assessments ..................................................................................................39 
13.2.1. 
Corneal Staining ................................................................................................39 
13.2.2. 
Snellen Visual Acuity (SVA) ...............................................................................39 


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13.2.3. 
Slit-lamp Exam (SLE) .........................................................................................39 
13.2.4. 
Intraocular Pressure (IOP) .................................................................................39 
13.2.5. 
COVID-19 Test (SARS-CoV-2) ..........................................................................39 
13.2.6. 
Demographics and Medical/Medication and Ocular History ...............................39 
13.2.7. 
Adverse Event Query/Concomitant Medication Query .......................................39 
14. ANALYSES AND REPORTS ............................................................................................40 
14.1. 
Final Integrated Report ..............................................................................................40 
15. STATISTICAL CONSIDERATIONS ..................................................................................40 
15.1. 
Statistical Plan ...........................................................................................................40 
15.2. 
Sample Size Calculation ............................................................................................40 
15.3. 
Analysis Populations..................................................................................................41 
15.4. 
Statistical Analyses ....................................................................................................41 
15.4.1. 
Analysis of the Primary Efficacy Endpoint(s) ......................................................41 
15.4.2. 
Analysis of the Secondary Endpoint(s) ...............................................................42 
15.4.3. Safety Analysis ..........................................................................................................42 
15.4.4. Interim Analyses ........................................................................................................42 
15.4.5. Sub-group Analyses ..................................................................................................42 
16. ADMINISTRATIVE STUDY RECORDS ............................................................................42 
16.1. 
Subject Enrollment and Identification .........................................................................42 
16.2. 
Study Charts/Records and Source Documents ..........................................................43 
16.3. 
Retention and Availability of Investigational Records .................................................43 
17. DRUG ACCOUNTABILITY ...............................................................................................44 
17.1. 
Product Shipment ......................................................................................................44 
17.2. 
Product Receipt .........................................................................................................44 
17.3. 
Product Storage .........................................................................................................44 
17.4. 
Drug Dose Package Labeling ....................................................................................44 
18. SUBJECT SAFETY MONITORING AND ADVERSE EVENTS .........................................44 
18.1. 
Subject Safety Monitoring ..........................................................................................44 
18.2. 
Pregnancy..........................................................................................................45 
18.3. 
Adverse Events .........................................................................................................45 
18.3.1. 
Recording Adverse Events .................................................................................46 
18.3.2. 
Reporting Serious Adverse Events ....................................................................47 
18.3.3. 
Removal of Subjects from Study ........................................................................48 


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18.3.4. 
Termination of Study Due to Adverse Events .....................................................49 
19. ETHICS OF CONDUCT ....................................................................................................49 
20. QUALITY CONTROL AND QUALITY ASSURANCE .......................................................49 
20.1. 
Pandemic COVID-19 Response Plan ........................................................................50 
21. REGULATORY .................................................................................................................50 
21.1. 
Institutional Review Board/ Health Canada ................................................................50 
21.2. 
Consent Document ....................................................................................................51 
21.3. 
Confidentiality ............................................................................................................52 
21.4. 
Investigator's Statement ............................................................................................52 
22. REFERENCES ..................................................................................................................54 
 


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1. LIST OF ABBREVIATIONS 
TERM 
DEFINITION  
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
DEC 
Dry eye Chamber 
DED 
Dry Eye Disease 
DMP 
Data Management Plan 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
 
 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LASIK 
Laser-assisted in situ keratomileusis 
MedDRA 
Medical Dictionary for Regulatory Activities 
ºC 
Degrees Celsius 
PI 
Principal Investigator 
QA 
Quality Assurance 
RASP 
Reactive Aldehyde Species 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SLE 
Slit-lamp examination 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unsuspected Serious Adverse Reaction 
SVA 
Snellen Visual Acuity 
USA 
United States of America 
VAS 
Visual Analog Scale 
WOCBP 
Women of Childbearing Potential 
 


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2. PRINCIPAL INVESTIGATOR 
 
  
  
  
 
  
 
 
 
3. SPONSOR REPRESENTATIVE 
                                                  
 
 
           
           
 
4. STUDY ADMINISTRATIVE STRUCTURE 
4.1. 
Clinical Research Organization 
 
 
4.2. 
Clinical Facilities 
 
 
 
 
 
 
4.3. 
Institutional Review Board (IRB) 
 
 
 
 
4.4. 
Safety Management  
 
 
 


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4.5 
Medical Monitor 
 
 


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5. STUDY SUMMARY 
Study Title 
 
A Randomized, Double-Masked, Vehicle-Controlled Crossover Clinical Trial to Assess 
Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in 
Subjects with Dry Eye Disease 
Protocol Number 
ADX-102-DED-027/C1D01748 
Study Phase 
Phase 2b 
Study Objectives 
To evaluate the efficacy of reproxalap, as assessed by conjunctival redness, Schirmer’s 
test, and ocular symptoms after dosing, prior to, and during exposure to the Dry Eye 
Chamber (DEC) in subjects with dry eye disease. 
Study Endpoints 
Primary Endpoints 
• 
Change from baseline in conjunctival redness on a 9-point scale (0-4) over 90 
minutes in the DEC at Visit 3 and Visit 5 
• 
Schirmer’s test change from baseline before and after the final dose at Visit 2 
and Visit 4 
Secondary Endpoints: 
• 
Schirmer’s test ≥10mm responder analysis before and after the final dose of 
Visit 2 and Visit 4 
• 
Visual analog scale (VAS) symptoms (dryness, discomfort, grittiness, burning, 
and stinging) assessed over 40 minutes and over 90 minutes in the DEC 
• 
Ocular itching score and VAS symptoms (dryness, discomfort, grittiness, 
burning, and stinging) assessed outside the DEC 
• 
Conjunctival redness assessed outside the DEC 
Safety Endpoints: 
• 
Snellen visual acuity (SVA) 
• 
Slit-lamp examination (SLE) 
• 
Adverse event (AE) query 
• 
Intraocular Pressure (IOP) 
Study Design 
Randomized, Double-Masked, Vehicle-Controlled, Crossover Clinical Trial to Assess 
Efficacy and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in 
Subjects with dry eye disease in a DEC. The clinical trial will consist of 6 visits to the 
clinic over a period of approximately 19 to 39 days.  


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Study Products 
and Treatment 
Product A (Investigational Product): 0.25% Reproxalap Ophthalmic Solution 
(reproxalap, manufactured by Aldeyra Therapeutics, Inc.) 
Product B (Vehicle): Vehicle Ophthalmic Solution (vehicle, manufactured by Aldeyra 
Therapeutics, Inc.) 
Treatments will be administered topically in both eyes 4 times at Visit 2 and Visit 4. 
Treatments will be administered 2 times at Visit 3 and Visit 5 (once at approximately time 
zero (-5 minutes) prior to DEC entry and once 45 minutes after initiation of the DEC. 
Route of 
Administration 
Ophthalmic (topical ocular administration of eye drops) 
Study Population 
Approximately 50 subjects with DED, ages 18 to 70 years, are expected to be enrolled 
in the trial.  
Study Conduct 
This clinical trial will have 6 visits, 2 in the Screening period (Visit 1a for medical 
screening and Visit 1b for DEC screening) and 4 visits in the Treatment periods. The 
first treatment period (Visits 2 and 3) will begin after at least a 7 to 14 day wash out post-
screening Visit 1b.  At Visit 2, subjects will be randomized to determine the order in which 
they will receive reproxalap or vehicle treatment. Subjects will receive the same study 
treatment on two consecutive days at Visit 2 (4 times) and Visit 3 (2 times). After a 
washout period of 7 to 14 days, subjects will return to the clinic for Treatment Period 2 
(Visits 4 and 5) and cross over to receive the other randomized treatment on two 
consecutive days at Visit 4 (4 times) and Visit 5 (2 times).  
Conjunctival redness will be assessed by trained study staff, whereas ocular dryness, 
itching, discomfort, burning, grittiness and stinging will be assessed by subjects
 
 at treatment visits. Visit 2 and 4 
will not include DEC exposure. Schirmer’s test will be conducted at Visit 2 and 4. Visit 3 
and Visit 5 will include DEC exposure and assessment of symptoms before and during 
exposure to DEC.  
Safety endpoint assessments will be performed throughout the study. Adverse events 
and concomitant medication will be recorded (refer to Schedule of Assessments).  
I. 
Visit 1a: Medical Screening (Day -21 to -8) 
All subjects will undergo a medical screening visit (Visit 1a), including written informed 
consent, demographics, medical/medication and ocular history. Corneal fluorescein 
staining and urine pregnancy (for all female subjects) test will be performed. 
II. 
Visit 1b: DEC Screening (Day -14 to -7) 
Medical/medication and ocular history will be updated for each subject. SVA and SLE 
will be performed pre- and post-DEC. IOP will be performed post-DEC. Vehicle will be 
administered in the clinic approximately 5 minutes prior to the DEC entry and after 45 
min in the DEC. Staff-assessed conjunctival redness will be performed approximately -
10 (+1) and -5 (+1) minutes pre-DEC entry and approximately at 10, 20, 30, 40, 55, 65, 
75, 85 and 90 minutes while in the DEC. Conjunctival redness will also be performed 
post-DEC (1 time within 15 minutes). Schirmer’s test (baseline) will be performed prior 
to DEC entry. Ocular itching score and all VAS ocular symptoms will be performed pre- 
and post-DEC. VAS assessments for ocular dryness, discomfort, burning, grittiness and 
stinging will be performed approximately -12 (+1) and -7 (+1) minutes prior to DEC entry 


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(and pre-vehicle administration) and approximately at 12, 22, 32, 42, 57, 67, 77, 87 and 
92 minutes while in the chamber. 
III. 
Visits 2 – Randomization and Baseline Treatment Visit 
Medical/medication and ocular history will be updated for each subject. A urine 
pregnancy test will be performed (for all female subjects). Subjects will be randomized 
to study treatments sequence (AB or BA). Study treatment will be administered 4 times 
as follows: Dose 1, Dose 2 (3 hours post dose 1), Dose 3 (30 min post Dose 2) and Dose 
4 (30 min post Dose 3). Schirmer’s test will be performed approximately 10 minutes pre-
Dose 4 and approximately 5 minutes post-Dose 4. Staff-assessed conjunctival redness, 
ocular itching score and VAS ocular symptoms will be performed at pre-dose and 
approximately 10 minutes after Dose 1, 2 and 3. 
IV. 
Visits 3 – DEC Treatment Visit 
Medical/medication and ocular history will be updated for each subject. Staff-assessed 
conjunctival redness will be performed approximately -10 (+1) and -5 (+1) minutes prior 
to DEC (and pre-treatment administration) and approximately at 10, 20, 30, 40, 55, 65, 
75, 85 and 90 minutes while in the DEC. Conjunctival redness will also be performed 
post-DEC (1 time within 15 minutes). Ocular itching score and VAS ocular symptoms 
will be performed pre- and post-DEC. VAS assessments for ocular dryness, discomfort, 
burning, grittiness and stinging  will be performed approximately -12 (+1) and -7 (+1) 
minutes prior to DEC entry (and pre-treatment administration) and approximately at 12, 
22, 32, 42, 57, 67, 77, 87 and 92 minutes while in the chamber. An SVA and SLE will be 
performed pre- and post-DEC. Pre-DEC SVA and SLE will be performed prior to 
symptom assessment. IOP will be performed post-DEC. The same treatment (as Visit 
2) will be administered in the clinic 2 times as follows: Dose 1 (administered 
approximately 5 min prior to DEC entry), Dose 2 (administered approximately 45 min 
into the DEC session). Subjects will be exposed to a DEC session (approximately 90 
minutes). 
V.          Visit 4 - Baseline Treatment Visit and Visit 5 – DEC Treatment Visit 
Visits 4 and 5 are similar to Visits 2 and 3, respectively. 
VI.          Follow-up Phone call follow-up 
For any subjects who withdraw/withdrawn prior to study exit, there will be a phone call 
within 7(+3) days to follow up on the subject’s health. 
Inclusion Criteria 
1. Eighteen (18) to 70 years of age at the time of screening (either gender and any 
race). 
2. Ability to provide written informed consent. 
3. Reported history of dry eye for at least 6 months prior to Visit 1a. 
4. Reported history of the use of eye drops for DED between 2 weeks to 6 months 
prior to Visit 1a. 
5. 
 
 
6. 
 


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Exclusion Criteria 
1. 
 
 
 
 
2. 
 
 
 
3. 
Diagnosis of an ongoing ocular infection (bacterial, viral, or fungal), active ocular 
inflammation, or history of inflammatory disease (that, in the opinion of the 
Investigator, could interfere with study conduct or assessments) at Visit 1a. 
4. 
Contact lens use within 7 days of Visit 1a or anticipate using contact lenses during 
the trial. 
5. 
 
 
6. 
Systemic corticosteroid or other immunomodulatory therapy (not including inhaled 
corticosteroids) within 60 days of Visit 1a, or any planned immunomodulatory 
therapy throughout the study period. 
7. 
 
 
 
 
8. 
 
9. 
Women of childbearing potential (WOCBP) who are pregnant and nursing. All 
female subjects must have a negative pregnancy test at Screening and Visits 2. 
10. If participant is of childbearing potential (female or male), unwillingness to use an 
acceptable means of birth control. (Acceptable methods of contraception are listed 
in section 10.3.3 and 10.3.4). 
11. Known allergy and/or sensitivity to  reproxalap or the drug product vehicle. 
12. A condition that the investigator feels may put the subject at significant risk, may 
confound the study results, or may interfere significantly with the subject’s 
participation in the trial. 
13. 
 
 
 
 


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16. 
 
 
17. Inability or unwillingness to follow instructions, including participation in all study 
assessments/procedures and visits. 
18. 
 
 
20. 
 
Statistical 
Analysis 
General Statistical Methods and Types of Analyses: 
Statistical analyses will be detailed in the statistical analysis plan (SAP), 
 
 Any changes to protocol stated analyses will 
also be detailed in the SAP. 
Sample Size: 
Approximately 160 subjects with dry eye disease will be screened in order to randomize 
approximately 50 subjects, and for approximately 50 subjects to complete the study. 
Approximately fifty (50) subjects will be assigned to each of two (2) treatment sequences, 
AB and BA.  
 
 
 
 
 
 
 
 
 
 
 
In order to account for dropout and to assess safety and the other secondary endpoints, 
a total of 50 subjects will be randomized. 
Primary Efficacy Analyses: 
The primary endpoints will be assessed using the ITT population with observed data 
only. The ITT population includes all randomized subjects. 
Reproxalap will be compared to vehicle for the primary efficacy endpoint of conjunctival 
redness. Treatment comparisons at pre-specified time points (every 10 minutes from 0 
to 90 minutes following chamber entry) will be performed 
 
 
 
Mean change from baseline (Visit 1b) of Schirmer’s test before and after Day 1 Dose #4 
will be assessed via a MMRM approach for a crossover study 
 
 
Sensitivity analyses for the primary analyses may include the following: 


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• 
 
 
 
 
 
 
 
Secondary Efficacy Analyses: 
Secondary efficacy endpoints will be analyzed by using a similar approach as the 
primary efficacy variables. Further details of the analysis plan will be described in 
statistical analysis plan document (SAP). 
Multiplicity Considerations: 
 
 
 
 
 
 
Safety Analysis 
Safety analysis will include descriptive analysis and listings according to received 
treatment. Safety analysis will be performed on all subjects receiving at least one dose 
of study medication. Subject’s safety data will be presented according to the treatment 
they actually received. The Safety population will be used for all analyses of safety 
endpoints as well as demographics and baseline characteristics. 


CLINICAL STUDY PROTOCOL 
 
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6. STUDY SCHEMATIC  
Table 6-1 Schedule of Assessments 


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Table 6-2 Schedule of Staff-Assessed Conjunctival Redness with DEC Exposure (Visit 1b1, 3, and 5) 
 
Time points in minutes 
DEC Time points 
(minutes) 
-10 
-5 
10 
20 
30 
40 
55 
65 
75 
85 
90 
Window (minutes) 
+1 
+5 
Visit 1b1, 3, and 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
First dose of treatment 
Second dose of treatment 
Table 6-3 Schedule of Subject-Assessed VAS Ocular Dryness, Discomfort, Burning, Grittiness and Stinging with 
DEC Exposure (Visit 1b1, 3, and 5) 
 
Time points in minutes 
DEC Time points 
(minutes) 
-12 
-7 
12 
22 
32 
42 
57 
67 
77 
87 
92 
Window (minutes) 
+1 
+3 
Visit 1b1, 3, and 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
First dose of treatment 
Second dose of treatment 
 


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7. INTRODUCTION 
7.1. 
Background and Study Rationale 
Dry eye disease (DED) is a common, multifactorial tear film and ocular surface disorder that 
causes eye pain and vision impairment. DED, also called keratoconjunctivitis sicca, is 
characterized by several symptoms of ocular discomfort, including but not limited to dry eye 
sensation, foreign body sensation, irritation, burning, tearing, ocular pain, and itching. Patients 
with DED may experience significant ocular discomfort and reduced visual function, resulting in a 
decreased quality of life or work productivity.1 DED is a globally prevalent disease that 
disproportionately affects older individuals (>50 years) and women. According to the Dry Eye 
Workshop II report, DED prevalence ranges from 5-50% worldwide, while several studies 
estimate prevalence in the 20–30% range, notably among individuals over 50 years old. The Dry 
Eye Workshop II meta-analysis corroborated prior findings that prevalence rises with age and is 
more prevalent in women than males. Dry eye symptoms were reported by 28.7% of surveyed 
patients in optometric clinics in the 1997 Canada Dry Eye Epidemiology Study (CANDEES). 
According to a recent survey, 21.3 percent of Canadians aged 18 and up have DED. 2,3 
For short-term treatment of DED, doctors typically give artificial tear eye drops and topical 
corticosteroids. Antibiotics (tetracyclines and macrolides), nonsteroidal anti-inflammatory drugs, 
autologous serum drops, omega fatty acids, mucin secretagogues, and anti-inflammatory drugs 
are used to treat DED symptoms. In addition, individuals with chronic DED are increasingly being 
prescribed prosthetic scleral lenses (i.e., PROSE) that also function as additional tear reservoirs 
to improve ocular surface hydration. Meibomian gland dysfunction, a major cause of evaporative 
dry eye illness, is frequently treated with hot eyelid compresses. Punctual plugs can be used to 
stop tear outflow in advanced cases of DED. To minimize tear evaporation in extreme cases of 
dry eye, tarsorrhaphy surgery, tear duct cauterization, or amniotic membrane transplantation may 
be required.4, 5 
 
 
 
 
 Given 
the severity, frequency, and complexity of DED, as well as the restricted modes of action by which 
these two compounds treat dry eyes, there is a medical need for more dry eye therapies, 
particularly those with multiple modes of action that target a larger dry eye population and are 
effective and safe for long-term daily usage.6,7 
Reproxalap is a novel, first-in-class aldehyde sequestering agent that binds rapidly and 
irreversibly to pro-inflammatory reactive aldehyde species (RASP). Topical ocular reproxalap has 
demonstrated clinical activity in Phase 2 and Phase 3 clinical trials in non-infectious anterior 
uveitis,8 allergic conjunctivitis,9 and DED.10, 11 Reproxalap has been administered to more than 
1200 subjects with no clinically significant safety concerns.  
Reproxalap topical ophthalmic solution is formulated as a sterile, preservative-free, aqueous 
solution for topical ocular delivery. Subjects are expected to self-administer 1 drop of 0.25% 
Reproxalap Ophthalmic Solution (reproxalap) or Vehicle. Direct instillation is the most efficient 


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method for delivery to the ocular surface and is an accepted and widely used method for topical 
application to the eye. This study will examine tolerability and activity of 0.25% Reproxalap 
Ophthalmic Solution versus Vehicle dosed once prior to entering dry eye chamber (DEC) in 
subjects with DED.12  
7.2. 
Nonclinical Data 
Inhibition of RASP by reproxalap has been studied under various in vitro conditions in which 
reproxalap has been shown to rapidly and irreversibly bind several common pro-inflammatory and 
cytotoxic RASP. The data suggest that RASP preferentially form covalent adducts with reproxalap 
under conditions that may mimic the physiologic milieu.  
Reproxalap has been well-tolerated in multiple non-clinical single-dose and repeat-dose 
pharmacology and toxicology studies in mice, rats, rabbits, dogs, and non-human primates, via 
topical ocular, intravitreal, topical dermal, oral, intraperitoneal, subcutaneous, and intravenous 
routes of administration. In a standard battery of genotoxicity tests, reproxalap was non-
mutagenic and non-clastogenic. Furthermore, no adverse effects of reproxalap were evident in in 
vivo central nervous system, respiratory, and cardiovascular safety pharmacology studies.  
Non-clinical pharmacokinetic studies have shown that topical ocular administered reproxalap is 
absorbed rapidly into ocular tissue and delivers potentially therapeutically relevant concentrations 
of reproxalap to the eye's anterior chamber while resulting in minimal systemic exposure.  
Overall, the non-clinical data suggest that reproxalap administered as a topical ophthalmic 
solution will continue to be safe, well-tolerated, and effective in clinical testing.12  
7.3. 
Effects in Humans 
 
 
 
 
 
 
 
 
 
 
7.4. 
Benefit/Risk Assessment 
 
 
 
 
 
 
 
 
 


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7.5. 
Rationale for Dose Selection 
Ophthalmic dosing is the optimal route of administration for ocular allergy treatments. The dosage 
and dosage regimen were selected based on previous data from non-clinical and clinical studies. 
0.25% reproxalap is the intended commercial formulation for allergic conjunctivitis and DED and 
is now in Phase 3 clinical testing for DED. 
 
8. OBJECTIVES AND ENDPOINTS 
8.1. 
Objectives 
To evaluate the efficacy of reproxalap, as assessed by conjunctival redness, Schirmer’s test, and 
ocular symptoms after dosing, prior to, and during exposure to the Dry Eye Chamber (DEC) in 
subjects with dry eye disease 
8.2. 
Endpoints 
8.2.1. Primary Endpoints 
 
Change from baseline in conjunctival redness on a 9-point scale (0-4) over 90 
minutes in the DEC at Visit 3 and Visit 5 
 
Schirmer’s test change from baseline before and after the final dose at Visit 2 and 
Visit 4 
8.2.2. Secondary Endpoints 
 
Schirmer’s test ≥10mm responder analysis before and after the final dose of Visit 
2 and Visit 4 
 
VAS symptoms (dryness, discomfort, grittiness, burning, and stinging) assessed 
over 40 minutes and over 90 minutes in the DEC 
 
Ocular itching score and VAS symptoms (dryness, discomfort, grittiness, burning, 
and stinging) assessed outside the DEC 
 
Conjunctival redness assessed outside the DEC 
8.2.3 
Safety Endpoints 
 
Snellen visual acuity (SVA) 
 
Slit-lamp examination (SLE) 
 
Adverse event (AE) query 
 
Intraocular Pressure (IOP) 
 


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9. STUDY DESIGN 
9.1. 
Overall Study Design 
This is a randomized, double-masked, vehicle-controlled, crossover clinical trial to assess efficacy 
and safety of 0.25% reproxalap ophthalmic solution compared to vehicle in subjects with dry eye 
disease in a DEC.  
This clinical trial will include 6 visits, 2 in the Screening period (Visit 1a for medical screening and 
Visit 1b for DEC screening) and 4 visits in the Treatment periods. The first treatment period (Visit 2 
and 3) will begin after at least a 7 to 14 days of wash out period post-screening Visit 1b. At Visit 
2, subjects will be randomized to determine the order in which they will receive Reproxalap and 
vehicle treatment. Subjects will receive the same study treatment at Visit 2 (4 times) and Visit 3 
(2 times), which will be scheduled on consecutive days. After a washout period of 7 to 14 days 
subjects will return to the clinic for Treatment period 2 (Visit 4 and 5) and cross over to receive 
the other treatment at Visit 4 (4 times) and Visit 5 (2 times) scheduled on consecutive days. 
Visit 2 and Visit 4 will not include DEC exposure. Schirmer’s test will be conducted at these visits. 
Visit 3 and Visit 5 will include DEC exposure and assessment of symptoms before, and during 
exposure to DEC). Conjunctival redness will be assessed by trained study staff, whereas ocular 
dryness, itching, discomfort, burning, grittiness and stinging will be separately assessed by 
subjects 
.  
Safety endpoint assessments will be performed throughout the study. Adverse events and 
concomitant medication will be recorded at each visit. 
 
 
 
 
 
 
Figure 9-1 Study Design 
 


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9.1.1. Dry Eye Chamber 
The DEC is a facility designed to control various environmental conditions 
 
 
 
 
 
 
 
 
9.1.2 
 
All DEC sessions (pre- and post-entry), assessments of signs and symptoms will be collected by 
qualified site staff and subjects 
 
 
10. SUBJECT SELECTION 
10.1. Number of Subjects 
Approximately 160 subjects with dry eye disease will be screened in order to randomize 
approximately 50 subjects, and for approximately 50 subjects to complete the study. 
Approximately fifty (50) subjects will be assigned to each of two (2) treatment sequences, AB and 
BA.  
10.2. Inclusion Criteria for Study Volunteers 
1. Eighteen (18) to 70 years of age at the time of screening (either gender and any race). 
2. Ability to provide written informed consent. 
3. Reported history of dry eye for at least 6 months prior to Visit 1a. 
4. Reported history of the use of eye drops for DED between 2 weeks to 6 months prior to 
Visit 1a. 
 
 
 
 
 
 
 
 


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10.3. Exclusion and Restriction Criteria for Study Volunteers  
10.3.1. Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded: 
 
 
 
 
 
 
 
3. Diagnosis of an ongoing ocular infection (bacterial, viral, or fungal), active ocular 
inflammation, or history of inflammatory disease (that, in the opinion of the Investigator, could 
interfere with study conduct or assessments) at Visit 1a. 
4. Contact lens use within 7 days of Visit 1a or anticipate using contact lenses during the trial. 
5. Previously had laser-assisted in situ keratomileusis (LASIK) surgery within 12 months of Visit 
1a and/or planned ocular and/or lid surgeries over the study period or any other ocular 
surgery within 6 months of Visit 1a. 
6. Systemic corticosteroid or other immunomodulatory therapy (not including inhaled 
corticosteroids) within 60 days of Visit 1a or any planned immunomodulatory therapy 
throughout the study period. 
 
 
 
 
9. Women of childbearing potential (WOCBP) who are pregnant and nursing. All female 
subjects must have a negative pregnancy test at Screening and Visits 2. 
 
 
 
11. Known allergy and/or sensitivity to reproxalap or the drug product vehicle. 
12. A condition that the investigator feels may put the subject at significant risk, may confound 
the study results or may interfere significantly with the subject’s participation in the trial. 
 
 
 
 


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17. Inability or unwillingness to follow instructions, including participation in all study 
assessments/procedures and visits. 
 
 
 
10.3.2. Restrictions and Concomitant Medications 
Once the study has begun, the subjects will be instructed to take only the study medication(s) 
described in this protocol. If the subject takes any other medication during the study, the 
Investigator will record the necessary information. 
Table 9.3.2-1: Restrictions and Concomitant Medications 


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Subjects who violate any of the above restrictions may be excluded or dropped from the study at 
the discretion of the Investigator. Individual exceptions to the above restrictions may be approved 
by the Investigator. 
10.3.3. Female Subjects of Childbearing Potential 
A female subject is considered of childbearing potential (WOCBP) if she is not post-menopausal, 
not congenitally sterile; not diagnosed as infertile (and not undergoing treatment to reverse 
infertility); or has not undergone successful surgical sterilization (such as tubal ligation, bilateral 
oophorectomy, or hysterectomy) completed at least 3 months prior to Screening. A woman is 
considered of non-childbearing potential if she is post-menopausal (if she is either amenorrheal 
for greater than 2 consecutive years, or naturally post-menopausal [no mense] for at least 1 year), 
surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy), congenital sterility, or 
diagnosed as infertile and not undergoing treatment to reverse infertility. 
WOCBP must use effective methods of birth control starting at least one month prior to the 
Medical Screening Visit 1a and until the last study procedure, such as total abstinence, hormonal 
or non-hormonal intrauterine device, a double-barrier method (Condom and diaphragm or cervical 
cap with spermicide (foam, cream, gel, sponge)), oral, transdermal, injected or implanted or 
hormonal contraceptive. A sterile sexual partner is not considered an adequate form of birth 
control. Subjects on hormonal contraceptives must have been on the same hormonal 
contraceptive for at least one month before the Screening Visit 1 and continue throughout the 
duration of the study. 
WOCBP will be instructed to contact the Investigator immediately if they suspect they might be 
pregnant. 
10.3.4. Male Subjects  
Male subjects must commit to not father a child or donate sperm from the first dose until the last 
dose. 
Male subjects (with female partners of childbearing potential) must commit to the consistent and 
correct use of at least two effective methods of birth control (as listed below) or total abstinence 
from the Medical Screening Visit 1a until the last administration of the investigational product. 
• 
Condom and diaphragm with spermicide (foam, cream, gel, sponge) 
• 
Condom and cervical cap with spermicide (foam, cream, gel, sponge) 
• 
Hormonal or non-hormonal intrauterine device (IUD) 
Female partner(s) of male volunteers also have the option to use the following highly effective 
hormonal method of contraception: oral, transdermal, implants, injectables contraceptives. 


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11. STUDY PRODUCT AND TREATMENT SEQUENCE 
11.1. Study Product and Treatment 
The following products will be used in the study: 
Product A: 0.25% Reproxalap Ophthalmic Solution (reproxalap) (Manufactured by Aldeyra 
Therapeutics, Inc.). 
Product B: Vehicle Ophthalmic Solution (vehicle) (Manufactured by Aldeyra Therapeutics, Inc.) 
Study treatment (reproxalap or vehicle) will be dosed topically in both eyes (1 drop in each eye). 
Study treatment will be administered 4 times (Dose 1, Dose 2 [3 hours post dose 1], Dose 3 [30 
min post Dose 2] and Dose 4 [30 min post Dose 3] at Visit 2 and Visit 4. Study treatment will be 
administered 2 times (Dose 1 [administered approximately 5 min Prior to DEC entry] and Dose 2 
[administered approximately 45 min into the DEC session]) at Visit 3 and Visit 5. 
11.2. Treatment Sequence 
The sequence in which subjects receive investigational product (reproxalap or vehicle) will be 
determined by randomization. 
 
 Randomization of subjects to one of the treatment sequences will be based on 
the randomization scheme. 
Subjects will be randomized to one of the two sequences: AB or BA. 
Sequence 
Treatment Period 1 
Treatment Period 2 
AB 
Reproxalap 
Vehicle 
BA 
Vehicle 
Reproxalap 
 
11.3. Masking and Unmasking 
11.3.1. Masking 
This is a double-masked clinical trial. The Sponsor, Investigators, qualified site personnel (except 
delegated unmasked pharmacy staff), and subjects will be masked to the investigational product 
administered until database lock. Only the delegated unmasked pharmacy staff and Scientific 
Affairs staff involved with preparing the assignment of Treatment A and B to the sequence will 
have access to the treatment under evaluation. 
11.3.2. Emergency Unmasking 
Emergency unmasking should only be performed when necessary to treat the subject. Most often, 
knowledge of the possible treatment assignments is sufficient to treat a clinical trial subject who 
presents with an emergency condition. 
The investigator should make every effort to contact the Medical Monitor to discuss the subject’s 
emergency and the need to unmask prior to unmasking any subject. 
In situations in which the investigator has tried but is unable to reach the Medical Monitor, best 
judgement on the part of the investigator should be used, based on the nature and urgency of the 
clinical situation, and may proceed with unmasking without having successfully reached and 
discussed the situation with the Medical Monitor. Once a subject's treatment assignment has been 


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unmasked, the Medical Monitor should be notified within 24 hours of the unmasking of the 
treatment, without revealing the treatment.  
Emergency unmasking envelopes (one envelope for each subject) will be prepared and verified 
by unmasked pharmacy staff using the randomization scheme. To facilitate emergency 
unmasking and ensure subject safety, the unmasking envelopes will be kept in a secured area 
with access limited to Pharmacy staff, the PI and other key designated study staff. Unmasking 
will be performed by breaking the seal of the envelope, for that specific subject of interest only, 
and retrieving the treatment code. 
The name of the unmasking person, the reason for unmasking, the subject randomization 
number, and the date and time of unmasking will be documented and confirmed by a signature. 
The reasons for and the date of unmasking must also be documented in the subject source 
document and the eCRF (if applicable). 
Any AE or Serious Adverse Event (SAE) associated with breaking the mask must be recorded 
and reported as specified in the protocol. The investigator has the responsibility to contact the 
Sponsor in the event of a drug-related, serious, unexpected AE, 
 or 
designee will be provided with the treatment assignment for the subject for regulatory reporting. 
If treatment assignment is unmasked, the treatment will be discontinued immediately, and the 
subject will be discontinued from the clinical trial.  
The mask may be broken in the case of pregnancy should the subject desire this information.  
12. STUDY VISITS 
12.1. COVID-19 Screening 
The following procedures will be performed as part of COVID-19 screening at each clinical visit: 
• 
Subjects will be pre-screened based on a COVID-19 questionnaire. 
• 
Body temperature will be measured. 
• 
A nasal swab will be collected for COVID-19 rapid testing at the beginning of each 
study visit except Visit 3 and 5 (Section 13.2.5).  
Subject’s further participation in the study will be based on the COVID-19 test results and 
procedures. 
12.2. Visit 1a: Medical Screening (Day -21 to -8) 
The following activities will be completed at Visit 1a: 
• 
A government-issued ID containing an image of the subject or a government-issued 
non-photo ID with a non-government photo ID of the subject will be used to confirm 
the subject’s identification at every visit. 
• 
Subjects will be asked to sign and date the Informed Consent Form. 
• 
Demographic data, including date of birth, gender, race, ethnicity, height and weight 
will be recorded.  


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• 
Medical/Medication and Ocular history will be completed for each subject (Section 
13.2.6). 
• 
Corneal fluorescein staining will be performed and evaluated using the 
 
(Section 13.2.1). 
• 
A urine pregnancy test will be performed (for all female subjects). Subjects with a 
positive result will be excluded. 
• 
The subjects will be evaluated for study inclusion, exclusion, and restriction criteria. 
Eligible subject will be scheduled to return for Visit 1b.  
12.3. Visit 1b: DEC Screening (Day -14 to -7) 
• 
The subjects will be evaluated for study inclusion, exclusion and restriction criteria.  
• 
Medical/medication will be updated for each subject. 
• 
An SVA and SLE will be performed pre- and post-DEC (Section 13.2.2 and 13.2.3). 
• 
IOP will be performed post-DEC (Section 13.2.4). 
• 
 training will be provided to the study participants. 
• 
Schirmer’s test (baseline) will be performed prior to vehicle administration before DEC 
entry (Section 13.1.2). 
• 
Vehicle will be administered in the clinic approximately 5 minutes prior to the DEC 
entry and 45 minutes after DEC entry.   
• 
Subjects will be exposed to a DEC session (approximately 90 minutes) 
• 
Staff-assessed conjunctival redness will be performed approximately -10 and -5 
minutes pre-DEC entry and approximately at 10, 20, 30, 40, 55, 65, 75, 85 and 90 
minutes while in the DEC (Section 13.1.1 and Table 6-2). Conjunctival redness will 
also be performed post-DEC (1 time) 
• 
Ocular itching score and VAS ocular symptoms (dryness, discomfort, burning, 
grittiness and stinging) will be assessed pre- and post-DEC. 
• 
VAS assessments for ocular symptoms (dryness, discomfort, burning, grittiness and 
stinging) will be performed approximately -12 and -7 minutes prior to DEC entry (and 
pre-vehicle administration) and approximately at 12, 22, 32, 42, 57, 67, 77, 87 and 92 
minutes while in the chamber (Section 13.1.3 and Table 6-3). 
• 
Adverse events and concomitants medications will be recorded during the visit. 
12.4. Visits 2 – Randomization and Baseline Treatment Visit 
Eligible subjects will return to clinic for the first treatment visit approximately 7 to 14 days after 
Visit 1b. The following activities will be performed: 
• 
Medical/medication will be updated for each subject. 
• 
The subjects will be evaluated for study inclusion, exclusion and restriction criteria.  


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• 
A urine pregnancy test will be performed (for all female subjects). Subjects with a 
positive result will be excluded. 
• 
Subjects will be randomized to study treatments sequence (AB or BA) (Section 11.2). 
• 
Study treatment will be administered 4 times as follows: Dose 1, Dose 2 (3 hours post 
dose 1), Dose 3 (30 min post Dose 2) and Dose 4 (30 min post Dose 3). 
• 
Staff-assessed conjunctival redness, ocular itching score and VAS ocular symptoms 
(dryness, discomfort, burning, grittiness and stinging) will be performed at pre-dose 
and approximately 10 (+2) minutes after Dose 1, 2 and 3. (Section 13.1.3 to 13.1.8). 
• 
Schirmer’s test will be performed approximately 10 (+2) minutes pre-Dose 4 and 
approximately 5 (+2) minutes post-Dose 4 (Section 13.1.2). 
• 
Adverse events and concomitants medications will be recorded during the visit. 
• 
Subjects will return to clinic the following day. 
12.5. Visits 3 – DEC Treatment Visit 
The following activities will be performed at Visit 3: 
• 
Medical/medication will be updated for each subject. 
• 
The subjects will be evaluated for study inclusion, exclusion and restriction criteria.  
• 
will be repeated for the study participants. 
• 
IOP will be performed post-DEC (Section 13.2.4). 
• 
An SVA and SLE will be performed pre- and post-DEC. Pre-DEC SVA and SLE will 
be performed prior to symptom assessment (Section 13.2.2 and 13.2.3). 
• 
Treatment (same as Visit 2) will be administered in the clinic 2 times as follows: Dose 
1 (administered approximately 5 min prior to DEC entry), Dose 2 (administered 
approximately 45 min into the DEC session). 
• 
Subjects will be exposed to a DEC session (approximately 90 minutes). 
• 
Staff-assessed conjunctival redness will be performed approximately -10 (+1) and -5 
(+1) minutes prior to DEC entry (and pre-treatment administration) and approximately 
at 10, 20, 30, 40, 55, 65, 75, 85 and 90 minutes while in the DEC (Section 13.1.1 and 
Table 6-2). Conjunctival redness will also be performed post-DEC (1 time). 
• 
Ocular itching score and VAS ocular symptoms (dryness, discomfort, burning, 
grittiness and stinging) will be assessed pre- and post-DEC. 
• 
VAS assessments for ocular symptoms (dryness, discomfort, burning, grittiness and 
stinging) will be performed approximately -12 (+1) and -7 (+1) minutes prior to DEC 
entry (and pre-treatment administration) and approximately at 12, 22, 32, 42, 57, 67, 
77, 87 and 92 minutes while in the chamber (Section 13.1.3 and Table 6-3). 
• 
Adverse events and concomitants medications will be recorded during the visit. 


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12.6. Visit 4 - Baseline Treatment Visit 
Subjects will return to Visit 4 after 7 to 14 days of Visit 3, and undergo the same procedures as 
Visit 2. 
12.7. Visit 5 – DEC Treatment Visit 
• 
Subjects will return to Visit 5 and undergo the same procedures as Visit 3. 
• 
Study exit 
12.8. Follow-up Phone call follow-up 
For any subjects who withdraw/withdrawn prior to study exit, there will be a phone call within 7(+3) 
days after they withdraw to follow up on the subject’s health. 
13. STUDY ASSESSMENTS AND PROCEDURES 
13.1. Efficacy Assessments 
For details regarding visits and timing of assessments and procedures, refer to Section 6.   
13.1.1. Staff Assessed Ocular Redness 


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13.1.2. Unanesthetized Schirmer’s Test 
Unanesthetized Schirmer tear test will be performed by trained study staff as per site SOP’s 
13.1.3. Visual Analog Scale (VAS) Ocular Dryness 
Visual Analog Scale (VAS) ocular dryness will be rated by the subjects 
 
 at designated timepoints during the study, using Visual 
analog scale score (0-100), where 0 represents none and 100 represents severe. 
 
. 
13.1.4. Ocular Itching score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.1.5. VAS Ocular Discomfort 
 
 
 
 
13.1.6. VAS Ocular Burning 
 
 
 
 
13.1.7. VAS Ocular Grittiness 
 
 
 
. 
13.1.8. VAS Ocular Stinging 
 
 


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13.2. Safety Assessments  
For details regarding visits and timing of procedures, refer to Section 6.  Safety measurements may be 
obtained at the discretion of the Investigator in addition to the safety assessments described in 
this section. 
13.2.1. Corneal Staining 
Corneal staining using fluorescein staining dye will be performed as per the site’s Standard 
Operating Procedure (SOP) and evaluated using the Oxford Scale.15 
13.2.2. Snellen Visual Acuity (SVA) 
SVA is a widely used metric for assessing the visual function that is sensitive to ophthalmic, 
retinal, and brain diseases. SVA chart contains lines, and each line contains five Sloan letters; 
the lines are all of the identical complexity, and the letter sizes increase geometrically from line to 
line. Each line on the chart has a similar assignment, with the font size being the only difference. 
Right and left eyes are tested using charts with distinct letter sequences. SVA will be measured 
per the site’s SOP. 
13.2.3. Slit-lamp Exam (SLE) 
The slit-lamp will be placed in front of the subject’s eyes and a narrow beam of bright light from 
the slit-lamp is directed into the eye. SLE observations will be graded as “normal” or “abnormal.” 
Abnormal findings will be categorized as clinically significant or not. The cornea, conjunctiva, 
anterior chamber, lens, and eyelid will be examined. 
13.2.4. Intraocular Pressure (IOP) 
The fluid pressure inside the eye is commonly known as IOP. IOP will be measured using non-
contact tonometry as per the site’s SOP. 
13.2.5. COVID-19 Test (SARS-CoV-2) 
At each visit, COVID-19 questionnaire, temperature checks and a nasal swab (at screening visits, 
Visit 2 and 4) will be collected at the clinical site for Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2). Subjects with a positive test result will be excluded/withdrawn from 
the study. 
13.2.6. Demographics and Medical/Medication and Ocular History 
The demographic data and a complete medical/medication and ocular history will be recorded at 
the Screening Visit. The following demographic information will be recorded: date of birth, gender, 
race, ethnicity, height, and weight. 
13.2.7. Adverse Event Query/Concomitant Medication Query 
The staff will record all adverse events observed, queried, or spontaneously volunteered by the 
subjects. An adverse event query will be performed as scheduled as per Investigator’s direction 
throughout the post-dose confinement period, prior to being released from confinement, and at 
each return visit for the study (if applicable). Subjects will be asked non-leading questions such 
as “How do you feel now?”, “How have you felt since last asked?” or “Have you taken any 


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medication since last asked?” If the presence of any symptom(s), adverse event(s), and/or 
concomitant medication is recorded, the clinical staff may advise the subjects to remain at the 
clinic site for safety reasons until the Investigator decides it is safe for the subjects to leave. If the 
subject decides to leave despite the Investigator's advice, he/she will be asked to sign a waiver. 
14.  ANALYSES AND REPORTS 
14.1. Final Integrated Report 
 
 
 It will contain a narrative description 
of the clinical and statistical procedures used during the conduct of the study. Appropriate tables 
and graphs will be created to summarize the data. 
The regulatory agency for submission will be Health Canada. The final integrated report may also 
be included in submissions to other international regulatory agencies. 
15. STATISTICAL CONSIDERATIONS 
15.1. Statistical Plan 
A statistical analysis plan (SAP) detailing the intended statistical analysis of the study data will be 
prepared as a separate document and finalized before database lock. Any deviation from the SAP 
will be described and justified in the final report, as appropriate. The procedure for accounting for 
missing, unused and spurious data will be included in the SAP. 
 
 
  
15.2. Sample Size Calculation 
Approximately 160 subjects with dry eye disease will be screened in order to randomize 
approximately 50 subjects, and for approximately 50 subjects to complete the study. 
Approximately fifty (50) subjects will be assigned to each of two (2) treatment sequences, AB and 
BA. 
 
 
 
 
 
 
 
 
 
In order to account for dropout and to assess safety and the other secondary endpoints, a total of 
50 subjects will be randomized.
 


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15.3. Analysis Populations 
The efficacy analyses of all efficacy endpoints will be carried out in the Intent-to-Treat (ITT) 
population. Supportive analyses may also be provided for conjunctival redness and Schirmer 
test endpoint(s) using the Per-Protocol (PP) population. 
The analysis populations as defined below: 
Safety Population 
All randomized subjects who use at least one dose of IP, 
regardless of whether clinical trial assessments were 
performed. 
Intent-to-Treat (ITT) Population 
All randomized subjects. Subjects are evaluated according 
to the IP treatment of the visit as per the randomized 
treatment sequence. 
Per-Protocol (PP) Population 
All ITT subjects will be considered PP if IP dosing occurs 
and there is not a major deviation from the protocol. 
The following is a list of protocol violations which may exclude subjects from the PP population:  
• 
Subject did not receive IP as assigned. 
• 
Subject did not meet all inclusion/exclusion criteria. 
15.4. Statistical Analyses 
15.4.1. Analysis of the Primary Efficacy Endpoint(s) 
The primary endpoints will be assessed using the ITT population with observed data only. The 
ITT population includes all randomized subjects. 
Reproxalap will be compared to vehicle for the primary efficacy endpoint of conjunctival redness. 
Treatment comparisons at pre-specified time points (every 10 minutes from 0 to 90 minutes 
following chamber entry) will be performed by using a Mixed Model Repeated Measures (MMRM) 
approach for a crossover study with baseline score as a covariate and correlated errors due to 
eye. 
Mean change from baseline (Visit 1b) of Schirmer’s test before and after Day 1 Dose #4 will be 
assessed via a MMRM approach for a crossover study 
 
 
Sensitivity analyses for the primary analyses may include the following: 
 
 
 
 
 
 
 
 
 


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15.4.2. Analysis of the Secondary Endpoint(s) 
Secondary efficacy endpoints will be analyzed by using a similar approach as the primary efficacy 
variables. Further details of the analysis plan will be described in statistical analysis plan 
document (SAP). 
Multiplicity Considerations:  
 
  
 
 
 
 
15.4.3. Safety Analysis 
Safety analysis will include descriptive analysis and listings according to received treatment. 
Safety analysis will be performed on all subjects receiving at least one dose of study medication. 
Subject’s safety data will be presented according to the treatment they actually received. The 
Safety population will be used for all analyses of safety endpoints as well as demographics and 
baseline characteristics. 
Adverse events and Serious Adverse Events (SAE) will be classified using standard Medical 
Dictionary for Regulatory Activities (MedDRA) 
 
 Summary tables listing the type, date of onset, date and time of resolution, 
incidence, severity, outcome, action taken, and Investigator’s opinion of relationship to the study 
product will be presented by treatment group for AEs reported after randomization. 
Concomitant medication used during the study will be listed by treatment and subject. 
15.4.4. Interim Analyses 
No interim analysis is planned at this point.  
15.4.5. Sub-group Analyses 
No sub-group analysis is planned at this point. 
16. ADMINISTRATIVE STUDY RECORDS 
16.1. Subject Enrollment and Identification  
Participants will be enrolled in the study prior to any screening procedures being performed. All 
participants will be assigned a unique subject identification number. This number will be used to 
identify their records until they are randomized into a treatment sequence. Participants who are 
randomized into the study will be assigned a unique randomization number. 


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16.2. Study Charts/Records and Source Documents 
A study chart/record will be maintained on-site for each subject to file records such as general 
observations, medical and medication use history, physical examination, clinical laboratory data 
source documents and related documentation. The original record will be considered the data 
‘source document’. The source documents will be available for inspection (direct/remote) by the 
study monitors and/or representatives before, during, or upon completion of the study. Good 
documentation practices will be followed for source documentation. All corrections will be dated 
and initialled. The Investigator will retain the originals. 
All clinical study data not available via electronic source will be collected by the Investigator and 
staff and recorded on source documents. The Investigator will assume responsibility for ensuring 
the completeness and accuracy of all clinical documents. 
This clinical trial will be conducted, and the data will be generated, documented (recorded), and 
reported in compliance with the protocol, GCP standards, ICH and other applicable local laws and 
regulations. 
All 
 staff will be appropriately trained to ensure the collection of accurate, 
consistent, complete, and reliable data are entered onto an electronic case report form (eCRF) 
unique for each subject. 
All data collected in the study will be captured and maintained in a secure and validated electronic 
data capture (EDC) system. 
staff will enter the data for each subject into an 
eCRF with the exception of the data collected in an electronic or paper source (e.g., lab data, 
diary data, etc.). Data source will be described in the Data Management Plan (DMP). 
The eCRF and/or diaries will contain edit checks and/or controls to ensure the quality, integrity, 
accuracy and completeness of the data entered. The Medical Monitor (medical representative) 
may examine eCRF and diary data for preliminary medical review (direct/remote). 
The eCRF data will be maintained in a validated study database with an audit trail of all changes 
that are made to the database, including the reason for the data change. AEs will be coded using 
a standard dictionary, Medical Dictionary for Regulatory Activities 
 while 
concomitant medications will be categorized using the World Health Organization Drug Dictionary 
(the most updated version of the dictionary) at the start of the study. 
Creation and validation of the EDC system and management of the data will be conducted. 
Methods used to ensure the quality and integrity of the data will be documented in the DMP, which 
will be approved by the Data Management provider and the Sponsor. 
16.3. Retention and Availability of Investigational Records 
 


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17. DRUG ACCOUNTABILITY 
All study product receipt, inventory, dispensing, dosing, and reconciliation records will be 
maintained in compliance with federal regulations. The study product will be dispensed to qualified 
study subjects according to established procedures.  
17.1. Product Shipment 
 
  
 
  
17.2. Product Receipt 
Upon receipt of drug supplies, the Investigator or designee will conduct an inventory and record 
the date received and the amount of drug received.  
17.3. Product Storage 
 
The Investigator will be responsible 
for maintaining accurate records of drug receipt, dispensing, and return. At the end of the study, 
all partially used and unused study products will be stored or disposed of as determined and 
agreed upon by the Sponsor and 
 
17.4. Drug Dose Package Labeling 
The study medication will be dispensed in individual subject’s kits and labeled with study-specific 
labels. Labels will reflect the use for the investigational purpose only, plus a unique number that 
will be used to identify each treatment for assigning the medication to each subject according to 
their randomized treatment assignment. 
18. SUBJECT SAFETY MONITORING AND ADVERSE EVENTS 
18.1. Subject Safety Monitoring  
Study staff will monitor the subjects throughout the study. Between the time interval of the study 
periods, staff will be available for subject queries. An Investigator will be on-site for dosing and 
on-call throughout the duration of the study. 
The Sponsor will designate qualified individuals to maintain a close liaison with the Investigator 
and study staff to ensure the clinical investigation follows the approved protocol and the research 
intent of GCP. Internal SOP for compliance with applicable government regulations will also be 
applied. This liaison will be documented by personal and/or telephone visits prior to study initiation 
and during the study to enable periodic reviews as well as clarify any questions, which may arise 
during the study. During on-site visits, Sponsor study monitors will be provided access to all study 
source documents to ensure the integrity of the data. Direct/remote access to such data during 


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the inspection or audits/monitoring of the study will be provided to IRB, Sponsor/ his 
representatives and regulatory authorities, but they must agree to respect the confidentiality of 
the data. 
18.2. Pregnancy 
Any female with a confirmed positive pregnancy result during study participation (from the time of 
signing the informed consent form until the end of the study) will be excluded from the study or 
immediately withdrawn from the study. Because of the possibility that the fetus/embryo could have 
been exposed to the study drug through the parent and for the subject safety, the subject will be 
followed until the end of the pregnancy (including spontaneous or voluntary termination). 
If a subject becomes pregnant or suspects that they became pregnant during the study or within 
30 days after the study is complete, they must notify the clinical site. 
The pregnancy will be recorded on a pregnancy form (provided by the clinical site) and reported 
to 
 IRB. In the absence of a pregnancy form, an adverse event form can 
be used. 
Attempts to contact the subject to inquire about the status and progression of the pregnancy will 
be made at intervals deemed appropriate (e.g., at least every three months) until an outcome of 
the pregnancy is known. This contact will be documented. 
 
18.3. Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug-related. AEs may include any changes in 
physical examination or laboratory parameters that are, in the Investigator's opinion, clinically 
significant changes.   
An SAE is defined as any AE that, in the view of either the Investigator or Sponsor, results in any 
of the following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
In-patient hospitalization or prolongation of existing hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 
Important medical events that may not result in death be life-threatening or require hospitalization 
may be considered an SAE 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.   
Life-threatening AE: 
Any AE that places the subject, in the view of either the 
Investigator or Sponsor, at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might 
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Unexpected AE: 
Any AE not listed in the applicable product information (e.g., drug 
product label or Investigator’s brochure) or that is not listed at the 
specificity or severity that has been observed.  
"Unexpected," as used in this definition, also refers to AEs that are mentioned in the applicable 
product information as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation. If such an unexpected AE is suspected to be related to the drug, then it is 
known as “Suspected Unexpected Serious Adverse Reactions (SUSARs)”. 
18.3.1. Recording Adverse Events 
The staff will record all AEs observed, queried, or spontaneously volunteered by the subjects 
(regardless of seriousness or relationship to study treatment) in the appropriate section of the 
subject’s case report form or source documents. Subjects experiencing AEs (including those 
withdrawn from the study due to an AE) will be followed until recovery to a satisfactory state, or 
stabilization, or appropriate outcome is established as judged by the Investigator. Exacerbation 
of conditions related to the signs and symptoms of Dry Eye will not be reported as an AE.  
The following details will be recorded for AEs: 
• 
Description of event/symptom 
• 
Onset date and time of event 
• 
End date and time of event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Action taken with study treatment noted as follows: 
 
Dose not changed 
 
Dose reduced 
 
Drug interrupted 
 
Drug withdrawn 
 
Not applicable 
 
Unknown 


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• 
Any other action taken (such as concomitant medication, non-drug therapy, hospitalization 
or none) 
• 
Outcome of AE noted as follows:  
 
Fatal 
 
Not recovered/not resolved 
 
Recovered/resolved 
 
Recovered/Resolved with sequelae 
 
Unknown 
• 
Causality noted as follows: 
Relationship to IP: The investigator must assess whether they consider an AE to be drug-related. 
In assessing this relationship, the investigator must use information about the drug as outlined in 
the Investigator’s Brochure, the subject’s pre-existent medical 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  
 
 
18.3.2. Reporting Serious Adverse Events 
AEs and medical history will be coded and classified according to the MedDRA, and AEs will be 
reported with respect to severity, duration, relationship to study drug(s) and action taken. 
Concomitant medications will be categorized using the World Health Organization Drug Dictionary 
(the most updated version of the dictionary) at the start of the study. 
All serious adverse experiences, whether deemed drug-related or not, will be reported to 
 preferably by email (or by telephone if email is not possible) immediately after 
the awareness by Investigator and in no case later than 24 hours, followed by a written report 
within 2 working days. The investigator is responsible for following all local regulations for the 
reporting of safety information, including the reporting of SAEs to their local IRB/Research Ethics 
Board (REB)/Independent Ethics Committee (IEC). 
The investigator must promptly report to his or her local IRB/REB/IEC all unanticipated problems 
involving risks to subjects. This includes death from any cause and all serious adverse events 
reasonably or possibly associated with the use of the investigational product.  
The Sponsor or their designee is responsible for appropriate reporting of relevant AEs, suspected 
unexpected serious adverse reactions (SUSARs) involving investigational product, to all 
regulatory authorities as per the below timeline:  


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• 
When neither fatal nor life-threatening, within 15 days after becoming aware of the 
information 
• 
When fatal or life-threatening, immediately when possible and, in any event, within seven 
(7) days after becoming aware of the information 
• 
Within eight (8) days after having informed Health Canada of the adverse drug reaction, 
submit a report that includes an assessment of the importance and implication of any 
findings 
In addition, the Sponsor or designee will be responsible for the submission of safety letters 
(e.g., SUSARs) to the central IRB/REB/IEC and participating investigators of all SUSARs 
involving IP according to applicable regulations.  
After termination of the clinical trial (determined as last subject, last visit), any unexpected safety 
issue that changes the risk-benefit analysis and is likely to have an impact on the subjects who 
have participated in it will be reported by the Sponsor as soon as possible to the competent  
authorities concerned together with proposed actions. 
The following Sponsor representative is to be contacted immediately following the occurrence of 
an SAE: 
 
 
 
18.3.3. Removal of Subjects from Study  
Subjects will be advised that they are free to withdraw from the study at any time for any reason 
or, if necessary, the Investigator may withdraw a subject from the study to protect the health of 
that subject. A subject may also be withdrawn for not complying with study procedures. The 
clinical report will include all reasons for early withdrawals. 
All subjects who receive at least one dose of either of the study products will be included in the 
safety analysis. If a subject terminates from the study early, all efforts will be made to complete 
all applicable safety procedures. In case of early termination, the Investigator will fully document 
the reason for early termination. Reasons for the early termination may include the following: 
• 
Voluntary withdrawal by subject. 
• 
Significant AE that led the Investigator or subject to withdraw for safety reasons. 
• 
Non-compliance with protocol requirements (e.g., use of restricted medication, not 
following dosing procedures, failure to make scheduled study visits in a timely 
fashion). 
• 
Pregnancy 


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• 
Participant enrolls in another clinical trial or is found to have previously enrolled in 
this clinical trial. 
• 
Positive COVID-19 test result. 
 
18.3.4. Termination of Study Due to Adverse Events 
If, in the opinion of the Sponsor, Regulatory authorities or the IRB, the incidence and severity of 
AE(s) outweighs the benefit of continuing the study, the study may be terminated.  
19. ETHICS OF CONDUCT 
This study will be conducted in compliance with the protocol and accordance with the appropriate 
guidelines and all applicable federal government codes, acts and regulations, the ethical 
principles that have their origins in the Declaration of Helsinki and all amendments, Good Clinical 
Practice (GCP) requirements, the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidance E6 (R2), and Tri-Council Policy 
Statement (Canada). Protocol and Informed Consent approval by the Ethics Board will be sought 
prior to the commencement of the study, and a copy of the Ethics attestation will be sent to the 
Sponsor.   
20. QUALITY CONTROL AND QUALITY ASSURANCE 
 will implement and maintain quality control procedures to ensure that the study 
is conducted, and that the data are generated, documented, and reported in compliance with the 
protocol, GCP and applicable regulatory documents. 
• 
All participant data relating to the study will be recorded on electronic CRF unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct/remote access to source data documents. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol, written SOPs, study-
specific plans and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Separate risk management plan will be developed prior to the start of the study in accordance 
with ICH E6 (R2). 


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20.1. Pandemic COVID-19 Response Plan 
Regulatory authorities have recognized that the Coronavirus Disease 2019 (COVID-19) pandemic 
may impact the conduct of the clinical study. COVID-19 pandemic has created a lot of uncertainty 
in the current situation and has put the subject’s safety, protocol compliance and data validity at 
high risk. 
Due to the COVID-19 pandemic, challenges may arise for clinical study conduct, for example, 
quarantines of site personnel/study participants, travel limitations, interruptions to the supply chain 
for the IP(s), or other considerations if site personnel or study participants become infected with 
COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures, 
including administration or use of the investigational product, housing duration or adhering to 
protocol specified visits and laboratory/diagnostic testing.  
To accommodate these challenges and mitigate safety risks associated with COVID-19, changes 
may be required from approved protocol which includes (but not limited to) conducting the study 
in multiple groups, change in study procedures timing, change in subject’s housing duration; 
ambulatory visits, additional test or parameter may be performed to standard inclusion or exclusion 
criteria at the discretion of Investigator/designee, etc. The changes made to the procedure will 
prioritize the subject’s safety and data validity and integrity. For any significant change, as per 
regulatory guidelines, a planned protocol deviation will be filled and notified to IRB and/or local 
regulatory (as applicable). 
All participants will be pre-screened prior to enrolment into the study and evaluated for risk factors 
and symptoms of COVID-19 according to the most recent regional Public Health guidelines 
available at the time of pre-screening. The screening is conducted through telephone at the time 
of appointment confirmation and again when the subject arrives at the clinic for any visit. 
Additional health checks, including body temperature or other vital sign monitoring, etc., may be 
performed during the study at the discretion of the Investigator/designee, even if not specified in 
the protocol. A subject who is tested positive to COVID-19 during the study will be withdrawn from 
the study. This subject and other subjects in close contact will be handled as per applicable local 
Public Health Guidelines. 
As the science and regulations are continuously being adapted to the evolving information around 
the pandemic, additional measures apart from the ones mentioned here may be undertaken to 
ensure subject safety and appropriate study conduct. The IRB would be informed for their review 
and approval as applicable.  
Risk Mitigation plan/Risk Evaluation and Mitigation strategy will be made to minimize the risk for 
COVID-19 exposure and to handle possible situations during the COVID-19 pandemic14.  
21. REGULATORY 
21.1. Institutional Review Board/ Health Canada 
The Investigator agrees to provide the IRB with all appropriate material, including a copy of the 
protocol, consent document, and advertising text (if study-specific advertising is used). The study 
will not be initiated without written IRB approval of the research plan and consent document. The 
Investigator will provide appropriate reports on the progress of this study to the IRB in accordance 
with applicable government and/or Institute regulations. The IRB will be informed of any 


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modifications of the protocol or consent document. Approval in writing will be obtained from the 
IRB prior to implementation of any changes which may increase subject risk or which may alter 
the validity or objectives of the data collected. A copy of the IRB approval letter covering such 
alterations will be maintained by the Sponsor. For modifications to the protocol which are 
administrative in nature or do not affect subject risk, the IRB will be notified in writing by the 
Sponsor. 
The Investigator must promptly report to the IRB all unanticipated problems involving risks to 
subjects. This includes AEs and other types of problems (i.e., AEs are a subset of unanticipated 
problems) that the Investigator is required to report to IRB.  
Sponsor should submit a notification to Health Canada indicating that the trial is complete. 
21.2. Consent Document 
A properly executed, written consent in compliance with current federal codes, GCP, acts and 
regulations and in accordance with ICH Guidance E6 on GCP shall be obtained from each subject 
prior to entering the trial or prior to performing any unusual or non-routine procedure involving risk 
to the subject. The consent document(s) to be used will be reviewed and approved by the 
Sponsor. It will be submitted by the Sponsor to the IRB for review and written approval prior to 
the start of the study. The Investigator shall provide a copy of the consent to the subject and a 
signed copy shall also be maintained in the study records. Attention is directed to the basic 
elements required in the consent document under current federal regulations for Protection of 
Human Subjects: 
1. A statement verifying the study involves research, an explanation of the purposes 
of the research, the expected duration of the subject's participation, a description 
of the procedures to be followed, and identification of any experimental 
procedures. 
2. A description of any reasonably foreseeable risks or discomforts to the subject.  
3. A description of any benefits to the subject or to others that may reasonably be 
expected from the research. 
4. A disclosure of appropriate alternative procedures or courses of treatment, if any, 
that might be advantageous to the subject. 
5. A statement describing the extent, if any, to which confidentiality of records 
identifying the subject will be maintained and noting the possibility the applicable 
regulatory agencies and the study Sponsor may inspect the records. 
6. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are 
available if injury occurs and, if so, what they consist of, or where further 
information may be obtained. 
7. An explanation of whom to contact for answers to pertinent questions about the 
research and research subject's rights and whom to contact in the event of a 
research-related injury to the subject. 
8. A statement that participation is voluntary and refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and the subject 


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may discontinue participation at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
Additional elements of consent, if appropriate, must be provided to the subject: 
1. A statement that the particular treatment or procedure may involve risks to the 
subject (or to the embryo or fetus, if the subject is or may become pregnant), which 
are currently unforeseeable. 
2. Anticipated circumstances under which the subject's participation may be 
terminated by the Investigator without regard to the subject's consent. 
3. Any additional costs to the subject that may result from participation in the study. 
4. The consequences of a subject's decision to withdraw from the research and 
procedures for orderly termination of participation by the subject. 
5. A statement that significant new findings developed during the course of the 
research that may relate to the subject's willingness to continue participation will 
be provided to the subject. 
6. The approximate number of subjects involved in the study. 
When seeking informed consent for applicable clinical trials, a statement may be provided to the 
subject that clinical trial information has been or will be submitted for inclusion in the clinical trial 
registry databank, if applicable. 
21.3. Confidentiality 
All information disclosed to the Investigator by the Sponsor or Sponsor designees shall be treated 
by the Investigators as strictly confidential. The Investigator will only use this information for the 
purpose of conducting the clinical trial described within this protocol. The Investigator must agree 
not to disclose any information contained within this protocol to any third party, except to those 
involved in the conduct of this clinical study and who are bound by the obligations of 
confidentiality. 
Information concerning the study treatment, patent applications, processes, unpublished scientific 
data, and other pertinent information is confidential and remains the property of the Sponsor. 
Details should be disclosed only to those involved in the approval or conduct of the study. It is 
understood that the Investigator will use the information obtained during the clinical study in 
connection with the development of the treatment and therefore may disclose it as required to 
regulatory agencies. The Investigator understands that he has an obligation to provide the 
Sponsor with all data obtained during the study. 
21.4. Investigator's Statement 
The Investigator agrees to conduct the trial as outlined in the approved protocol and in accordance 
with the 
 guidelines and all applicable federal government codes, acts and regulations, 
GCP requirements and ICH guidance E6 (R2) on Good Clinical Practice. These GCP guidelines 
include, but are not limited to: 
1. Permission to allow 
or applicable regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner that 


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ensures subject confidentiality. If this study is to be inspected by a regulatory agency, 
 will be notified as soon as possible. 
2. Submission of the proposed clinical investigation, including the protocol, consent 
document, and advertising text (if study-specific advertising is used) to a duly constituted 
IRB for approval and acquisition of written approval for each, prior to study initiation. 
3. Use of a written consent document obtained prior to entry into the study or prior to the 
performance of any non-routine procedures that involve subject risk. The consent 
document(s) must contain all the elements specified in the federal regulations and have 
been previously approved by 
and the IRB. 
4. Submission of any proposed change in or deviation from the protocol to the IRB, using 
a signed formal amendment document prepared by 
 Investigator. If the 
change or deviation increases the risk to the study population or adversely affects the 
validity of the clinical investigation or the subject’s rights, IRB approval must be obtained 
prior to implementation. IRB will be notified regarding changes that do not involve risk or 
affect the validity of the investigation or the subject’s rights. 
5. Documentation and explanation of protocol deviations will be made on the appropriate 
case report form page, source document or by written documentation to 
 
6. The Investigator shall promptly report to the 
any severe adverse event that may 
reasonably be regarded as caused by, or probably caused by, the study treatments. 
7. The Investigator shall submit timely progress reports to the IRB and
 at 
appropriate intervals, but not to exceed one year. The final report will be submitted to the 
IRB within 4 months after study completion, termination, or discontinuation. 
8. The Investigator and study staff shall maintain accurate source documents from which 
case report form data or source documents are based and accountability records that 
show the receipt and disposition of all study treatment(s) shipped to the Investigator. 
9. When new information is relevant to participants’ welfare, Investigator must promptly 
inform all participants to whom the information applies that requires to be reported to 
Health Canada as well.  
The Investigator agrees that all information provided by the 
 (including pre-clinical data) 
protocols, case reports from data or source documents, and verbal and written information will 
be kept strictly confidential and confined to the personnel involved in conducting the trial. It is 
recognized this information may be given in confidence to the IRB. 
 
 


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22. REFERENCES  
1. The Definition and Classification of Dry Eye Disease: Report of the Definition and 
Classification Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf. 2007; 
5(2): 75-92. doi:10.1016/s1542-0124(12)70081-2.  
2. Caffery B, Srinivasan S, Reaume CJ, et al. Prevalence of dry eye disease in Ontario, Canada: 
A population-based survey. Ocul Surf. 2019; 17(3): 526-531. doi:10.1016/j.jtos.2019.02.011.  
3. Chan CC, Prokopich CL. Lifitegrast Ophthalmic Solution 5.0% for Treatment of Dry Eye 
Disease: Overview of Clinical Trial Program. J Pharm Sci. 2019; 22(1): 49-56. doi: 
10.18433/jpps29895. 
4. Phadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on 
Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future 
Challenges. Advances in Pharmaceutics. 2015: 1-12. doi:10.1155/2015/704946 
5. Lin H, Yiu SC. Dry eye disease: A review of diagnostic approaches and treatments. Saudi J 
Ophthalmol. 2014; 28(3): 173-81. doi: 10.1016/j.sjopt.2014.06.002. 
6. 
PrRestasis 
MultiDose™, 
(Cyclosporine 
Ophthalmic 
Emulsion 
0.05% 
w/v), 
Anti-
Inflammatory/Immunomodulator. Allergan Inc, Monograph. June 1, 2018. 
7. 
PrXidra®, Lifitegrast Ophthalmic Solution 5% (w/v), Lymphocyte function associated antigen-
1 (LFA-1) antagonist. Novartis Pharmaceuticals Canada Inc, Monograph. November 21, 
2019. 
8. Mandell KJ, Clark D, Chu DS, Foster CS, Sheppard J, Brady TC. Randomized Phase 2 Trial 
of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious 
Anterior Uveitis: Model for Corticosteroid Replacement. J Ocul Pharmacol Ther. 2020; 
36(10): 732-739. doi: 10.1089/jop.2020.0056. 
9. Clark D, Cavanagh B, Shields AL, Karpecki P, Sheppard J, Brady TC. Clinically Relevant 
Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 
ALLEVIATE 
Trial. 
Am 
J 
Ophthalmol. 
2021; 
S0002-9394(21)00222-1. 
doi: 
10.1016/j.ajo.2021.04.023 
10. Clark D, Tauber J, Sheppard J, Brady TC. Early Onset and Broad Activity of Reproxalap in a 
Randomized, Double-Masked, Vehicle-Controlled Phase 2b Trial in Dry Eye Disease. Am J 
Ophthalmol. 202; 226:22-31. doi: 10.1016/j.ajo.2021.01.011 
11. Clark D, Sheppard J, Brady TC. A Randomized Double-Masked Phase 2a Trial to Evaluate 
Activity and Safety of Topical Ocular Reproxalap, a Novel RASP Inhibitor, in Dry Eye Disease. 
J Ocul Pharmacol Ther. 2021; 37(4): 193-199. doi: 10.1089/jop.2020.0087 
12. Reproxalap (ADX-102) Topical Ophthalmic Solution Investigator’s Brochure, Edition 7.0, 
Dated 12 Feb 2021. 
13. Schulze MM, Jones DA, Simpson TL. The development of validated bulbar redness 
grading 
scales. 
Optom 
Vis 
Sci. 
2007; 
84(10): 
976-983. 
doi: 
10.1097/OPX.0b013e318157ac9e 


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14. COVID-19 for health professionals. Peel Region. https://www.peelregion.ca/health-
professionals/covid-19/. Accessed Jan 21, 2022.  
15. Oxford Grading System. https://www.aao.org/image/oxford-grading-system. Accessed Jan 
20, 2022. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN  
A Randomized, Double-Masked, Vehicle-Controlled Crossover 
Clinical Trial to Assess Efficacy and Safety of 0.25% Reproxalap 
Ophthalmic Solution Compared to Vehicle in Subjects with Dry Eye 
Disease 
 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
 
 
 
Protocol Number: 
ADX-102-DED-027 
 
 
   
 
 
 
 
 
 
 
 
Date:    
 
14-Jun-2022 
Version:  
 
1.0 
 
 
 
 
 
 
 
 
 
 


 
 
Page 2 of 27 
A Randomized, Double-Masked, Vehicle-Controlled Crossover Clinical Trial to Assess Efficacy 
and Safety of 0.25% Reproxalap Ophthalmic Solution Compared to Vehicle in Subjects with Dry 
Eye Disease 
 
 
Protocol Number: 
ADX-102-DED-027 
Version:  
 
1.0  
Date:    
 
14-Jun-2022 
 
 
Statistical Analysis Plan Approval 
 
 
 
 


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Table of Contents 
1. 
Introduction .............................................................................................................................. 6 
2. 
Summary of Statistical Deviations from the Protocol ............................................................... 6 
3. 
Study Objectives ...................................................................................................................... 6 
4. 
Study Variables ........................................................................................................................ 7 
4.1 Efficacy Variables .................................................................................................................... 9 
4.1.1 
Primary Endpoints: ........................................................................................................... 9 
4.1.2 
Secondary Endpoints: ...................................................................................................... 9 
4.2 Safety Variables ....................................................................................................................... 9 
5. 
Study Design and Procedures ................................................................................................. 9 
5.1  General Study Design .............................................................................................................. 9 
5.2  Schedule of Visits and Assessments ..................................................................................... 10 
5.3  Inclusion – Exclusion Criteria and General Study Population ............................................... 10 
6. 
Study Treatments ................................................................................................................... 11 
6.1  Method of Assigning Subjects to Treatment Condition .......................................................... 11 
6.2  Masking and Unmasking ........................................................................................................ 11 
7. 
Sample Size and Power Considerations ............................................................................... 12 
8. 
Data Preparation .................................................................................................................... 13 
9. 
Management of Analysis Data ............................................................................................... 14 
9.1  Covariates and Subgroups .................................................................................................... 14 
9.1.1 
Planned Covariates ........................................................................................................ 14 
9.1.2 
Subgroups ...................................................................................................................... 14 
9.2  Interim Analyses .................................................................................................................... 14 
9.3  Handling of Early Termination Visit Information ..................................................................... 15 
9.4  Pooling of Study Centers ....................................................................................................... 15 
9.5  Missing Data .......................................................................................................................... 15 
9.5.1 
Handling of Missing Date Values ................................................................................... 15 
10. 
Analysis Populations .............................................................................................................. 16 
10.1  
Intent-to-Treat ................................................................................................................ 16 
10.2  
Per Protocol ................................................................................................................... 16 
10.3  
Safety ............................................................................................................................. 16 
11. 
General Statistical Considerations ......................................................................................... 16 
11.1 Unit of Analysis ...................................................................................................................... 16 
11.2 Missing or Inconclusive Data Handling .................................................................................. 17 
11.3  
Definition of Change Score ............................................................................................ 17 


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12.    Disposition of Subjects ............................................................................................................. 17 
13. 
Demographic, Body Habitus and Pretreatment Variables ..................................................... 18 
13.1  
Demographic and Body Habitus Variables .................................................................... 18 
13.2  
Pretreatment Variables .................................................................................................. 18 
14. 
Medical History and Concomitant Medications ...................................................................... 18 
14.1  
Medical History............................................................................................................... 18 
14.2  
Concomitant Medications ............................................................................................... 18 
15. 
Dosing Compliance and Treatment Exposure ....................................................................... 19 
15.1 Dosing Compliance ................................................................................................................ 19 
15.2 Treatment Exposure .............................................................................................................. 19 
16. 
Efficacy Analyses ................................................................................................................... 19 
16.1 Analysis of the Primary Efficacy Endpoint(s) ......................................................................... 19 
16.2 Analysis of the Secondary Endpoints and Secondary Analyses of Primary Endpoints ........ 20 
16.3 Multiplicity Considerations ..................................................................................................... 21 
17. 
Safety Analysis ...................................................................................................................... 21 
17.1 Deaths, Serious Adverse Events and Other Significant Adverse Events .............................. 23 
17.1.1 
Deaths ........................................................................................................................ 23 
17.1.2 
Serious Adverse Events ............................................................................................. 23 
17.1.3 
Adverse Events Leading to Discontinuation of Study Drug or Withdrawal from Study23 
18. 
Other Safety Variables ........................................................................................................... 24 
18.1 Visual Acuity (ETDRS) ........................................................................................................... 24 
18.2 Slit-Lamp Biomicroscopy Examination .................................................................................. 24 
18.3 Intraocular Pressure (IOP) ..................................................................................................... 24 
19. 
Additional Analyses ................................................................................................................ 25 
20. 
Revision History ..................................................................................................................... 25 
21. 
Reporting Conventions .......................................................................................................... 25 
21.1 General Reporting Conventions ............................................................................................ 25 
21.2 Population Summary Conventions ........................................................................................ 26 
22. 
References ............................................................................................................................. 27 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCVA 
Best Corrected Visual Acuity 
CI 
Confidence Interval 
CFB 
Change From Baseline 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DEC 
Dry Eye Chamber 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
OSDI 
Ocular Surface Disease Index 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAAS 
Software-as-a-Service 
SAE 
Serious Adverse Event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TE-SAE 
Serious Treatment-Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time 
VA 
Visual Acuity 
WHO 
World Health Organization 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the statistical analyses to be applied to 
data resulting from study protocol ADX-102-DED-027, version 1.0 dated 04Feb2022. Although the 
primary objective of the SAP is to detail the statistical procedures that will be used, various other details 
have been selectively included.  These details convey aspects of the experimental design and study 
procedure considered to be important to a fully informed understanding of the context underlying the 
analyses, and therefore the aim and purpose of the analyses. 
This SAP has been written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (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 (CSR). 
 
 
 
 
  
Additional analyses other than the planned analyses described herein may be conducted as ad-hoc 
analyses.  All ad-hoc analyses will be identified in the CSR. The intent of any such analyses would be 
to better characterize treatment effects. 
2. Summary of Statistical Deviations from the Protocol  
Analyses outlined in this SAP are in all instances thought to be compatible with or complimentary to the 
more general presentation found in the protocol. 
3. Study Objectives 
The general study objective is to evaluate the efficacy of reproxalap in subjects with dry eye disease, as 
assessed by conjunctival redness, Schirmers test, and ocular symptoms.  
 
  
 
 
 
 
 


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4. Study Variables 
Efficacy variables and safety variables follow.  Prior to a listing of each variable, the Study Schematic from the protocol has been inserted.  This schematic 
summarizes the variables that will be collected and conveys important features of the experimental design that further inform the collection of variables. 
 


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4.1 
Efficacy Variables 
The efficacy variables include the following: 
4.1.1 
PRIMARY ENDPOINTS: 
• 
Change from baseline in Schirmers test prior to and after the final of four doses at visit 2 and 
visit 4.  
• 
Change from baseline in conjunctival redness on a 9-point scale (0-4) over 90 minutes in the 
DEC at visit 3 and visit 5.   
4.1.2 
SECONDARY ENDPOINTS:  
• 
Responder event rate where “response” is defined as a Schirmers test of ≥10mm that is 
assessed before and after the final dose at both visit 2 and visit 4.  
• 
Conjunctival Redness measured at designated times outside the DEC 
• 
VAS for ocular dryness, discomfort, burning, grittiness, and stinging measured at designated 
times for all visits 
4.2 
Safety Variables 
The safety variables include the following: 
• 
Snellen visual acuity (SVA) 
• 
Slit-lamp examination (SLE) 
• 
Intraocular pressure (IOP) 
• 
Adverse event (AE) query 
• 
Concomitant Medications 
• 
Intraocular Pressure (IOP) 
5. 
Study Design and Procedures 
5.1  
General Study Design 
This is a Phase 2b, randomized, double-masked, vehicle-controlled, crossover clinical trial to assess 
efficacy and safety of 0.25% reproxalap ophthalmic solution compared to vehicle in subjects with dry 
eye disease.  Assessments are carried out both within and without DEC presence. The clinical trial will 
consist of 6 visits to the clinic over a period of approximately 19 to 39 days.  
 
 
 
 
 


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Study visits will be referred to in all tables and listings as the expected study day corresponding to the 
visit to enable reviewers to understand the assessment timing without referring to the protocol visit 
schedule.  The following table 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. 
Scheduled Visit 
Planned Study Day 
 
 
Visit 1a 
Day -21 
 
 
 
Visit 1b 
Day -14 
 
 
Visit 2 
Day 1 
 
 
   
Visit 3 
Day 2 
 
 
 
 
 
 
Visit 4 
Day 10 
 
 
 
Visit 5 
Day 11 
 
 
 
 
 
 
 
 
 
 
5.2  
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided along with other features of the experimental design 
in the Protocol Study Schematic located on pages 7 and 8 of this document. 
5.3  
Inclusion – Exclusion Criteria and General Study Population  
The inclusion and exclusion criteria are enumerated and described in the protocol and have not been 
repeated in this SAP. The inclusion and exclusion criteria apply to all subjects.    
 


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6. Study Treatments 
6.1  
Method of Assigning Subjects to Treatment Condition 
Before the initiation of study at Screening Visit 1a, each subject who provides written and informed 
consent will be assigned to a screening number. All screening numbers will be assingned 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 1a/b 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. 
Randomization and kit numbers will be assigned automatically to each subject as they are entered into 
the IWRS.   
The sequence in which subjects receive investigational product (reproxalap or vehicle) will be 
determined by randomization. 
 
Randomization of subjects to one of the treatment sequences will be based on the 
randomization scheme. 
Subjects will be randomized to one of two sequences: AB or BA. 
Sequence 
Treatment Period 1 
Treatment Period 2 
AB 
Reproxalap 
Vehicle 
BA 
Vehicle 
Reproxalap 
The randomization schedule will use block randomization, such that there will be an approximately equal 
number of subjects assigned to each of the two treatment sequences. Both the randomization number 
and the dispensed study drug kit number(s) will be recorded on the subject’s source document and 
eCRF. The Sponsor, investigators, and study staff will be masked during the randomization process and 
throughout the study. 
6.2  
Masking and Unmasking 
In general, the final, open statistical analysis will be performed without the possibility of data alteration.  
Procedures to insure this are described in some detail in what follows. 
The Sponsor, investigators, qualified site personnel (except delegated unmasked pharmacy staff), and 
subjects will be masked to the investigational product administered 
 
 
 
  
 


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Emergency unmasking should only be performed when necessary to treat the subject. Most often, 
knowledge of the possible treatment assignments is sufficient to treat a clinical trial subject who presents 
with an emergency condition. 
The investigator shall make every effort to contact the Medical Monitor to discuss the subject’s 
emergency and the need to unmask prior to unmasking any subject. 
In situations in which the investigator has tried but is unable to reach the Medical Monitor, best judgment 
on the part of the investigator should be used, based on the nature and urgency of the clinical situation.  
Pending appropriate conditions, the investigator may proceed with unmasking without having 
successfully reached and discussed the situation with the Medical Monitor. Once a subject's treatment 
assignment has been unmasked, the Medical Monitor should be notified within 24 hours of the 
unmasking of the treatment, without revealing the treatment.  
If the investigator determines that emergency unmasking is necessary, the investigator should identify 
the given subject’s IP kit, which contains a scratch-off laminate under which the treatment is identified, 
along with the associated lot number. In order to unmask, the investigator should scratch off the 
laminate, using a flat object and applying pressure, to reveal the treatment assigned for that subject.   
The emergency unmasking should be performed by the designated site personnel. The investigator 
must also indicate in source documents and the Case Report Form (CRF) that the mask was broken 
and provide the date, time, and reason for breaking the mask.  
Any AE or Serious Adverse Event (SAE) associated with breaking the mask must be recorded and 
reported as specified in the protocol. The investigator has the responsibility to contact the Sponsor in 
the event of a drug-related, serious, unexpected AE. 
 will be provided 
with the treatment assignment for the subject for regulatory reporting. 
If treatment assignment is unmasked, the treatment will be discontinued immediately, and the subject 
will be discontinued from the clinical trial.  
The mask may be broken in the case of pregnancy should the subject desire this information. 
7. Sample Size and Power Considerations 
Approximately 160 subjects with dry eye disease will be screened in order to randomize and realize 
study completion in approximately 50 subjects.  Approximately 25 subjects will be assigned to one of 
two (2) treatment sequences, namely, AB (reproxalap then vehicle) or BA (vehicle then reproxalap). 
 


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In order to account for dropout and to assess safety and the other secondary endpoints, a total of 50 
subjects will be randomized. 
  
8. Data Preparation 
A study chart/record will be maintained on-site for each subject to file records such as general 
observations, medical and medication use history, physical examination, clinical laboratory data source 
documents, and related documentation. The original record will be considered the data ‘source 
document’. The source documents will be available for inspection (direct/remote) by the study monitors 
and/or representatives before, during, or upon completion of the study. Good documentation practices 
will be followed for source documentation. All corrections will be dated and initialed. The Investigator 
will retain the originals. 
All clinical study data not available via electronic source will be collected by the Investigator and staff 
and recorded on source documents. The Investigator will assume responsibility for ensuring the 
completeness and accuracy of all clinical documents. 
This clinical trial will be conducted, and the data will be generated, documented (recorded), and reported 
in compliance with the protocol, GCP standards, ICH, and other applicable local laws and regulations. 
 staff will be appropriately trained to ensure the collection of accurate, consistent, 
complete, and reliable data are entered onto an electronic case report form (eCRF) unique for each 
subject. 
All data collected in the study will be captured and maintained in a secure and validated electronic data 
capture (EDC) system. 
 staff will enter the data for each subject into an eCRF, with 
the exception of the data collected in an electronic or paper source (e.g., lab data, diary data, etc.). Data 
source will be described in the Data Management Plan (DMP). 


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The eCRF and/or diaries will contain edit checks and/or controls to ensure the quality, integrity, 
accuracy, and completeness of the data entered. The Medical Monitor (medical representative) may 
examine eCRF and diary data for preliminary medical review (direct/remote). 
The eCRF data will be maintained in a validated study database with an audit trail of all changes that 
are made to the database, including the reason for the data change. AEs will be coded using a standard 
dictionary, Medical Dictionary for Regulatory Activities 
 while concomitant 
medications will be categorized using the World Health Organization Drug Dictionary 
 
at the start of the study. 
Creation and validation of the EDC system and management of the data will be conducted. Methods 
used to ensure the quality and integrity of the data will be documented in the DMP, which will be 
approved by the Data Management provider and the Sponsor. 
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 
 
and Aldeyra Therapeutics, Inc. personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined; and 
• 
Randomized treatment codes have been unmasked. 
 
9. Management of Analysis Data  
9.1  
Covariates and Subgroups 
9.1.1 
PLANNED COVARIATES 
 
 
    
9.1.2 
SUBGROUPS 
None are planned.  
9.2  
Interim Analyses 
No interim analyses are planned. 


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9.3  
Handling of Early Termination Visit Information 
 
 
  
9.4  
Pooling of Study Centers 
 
9.5  
Missing Data  
 
 
  
9.5.1 
HANDLING OF MISSING DATE VALUES  
9.5.1.1 Partial or Missing Dates  
 
 
 
  
 
  
 
 
   
 
  
 
 
 
  
 
   
  
 
  
 
 
 
  
 
 
  
 
 
  
 
  


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10. Analysis Populations 
Analysis populations include the intent-to-treat (ITT) population, the per-protocol (PP) population, and 
the safety population.  The statistical analysis of safety data will be performed on the safety population. 
The analysis of efficacy data will be performed on the ITT population and on the PP population to provide 
sensitivity analyses. 
10.1  
Intent-to-Treat 
The ITT population includes all randomized subjects. Subjects in the ITT population will be analyzed as 
randomized.  
10.2  
Per Protocol 
The PP population includes subjects in the ITT population subject who received at least one dose of IP 
who met all inclusion/exclusion criteria, and who did not incur a major protocol deviation. Protocol 
deviations will be assessed prior to database lock and unmasking. Subjects in the PP population will be 
analyzed as treated.  
10.3  
Safety 
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.  
 
11. General Statistical Considerations 
11.1 
Unit of Analysis  
 
   


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11.2 
Missing or Inconclusive Data Handling 
Minimal data loss is anticipated and a need for imputation applied to missing values and/or other 
procedures (e.g., tipping point analysis) is not expected.  
 
    
11.3  
Definition of Change Score 
 
 
  
12.    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.  
 
 
  This information will be presented for the ITT, PP, and Safety populations.  In 
general, percentages will be calculated using randomized subjects as the denominator (with any 
exceptions noted). 
 
The reasons for study 
discontinuation that will be summarized include AE, protocol deviation, administrative reasons (e.g., 
inability to continue, lost to follow up), Sponsor termination of 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 sequence, 
period, treatment ignoring sequence, and all subjects, 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 SAE / AE, Visit Out of Window, Subject’s Non-compliance with Test Article, 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 and description of each deviation. 
 
. 


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13. Demographic, Body Habitus and Pretreatment Variables 
13.1  
Demographic and Body Habitus Variables 
The demographic and body habitus variables collected in this study include age, sex, race, ethnicity, 
height, and weight.  
 
 
Age (years) will be summarized using continuous descriptive statistics.  Further, age will be categorized 
as follows: <65 years and ≥65 years. Age will be reported in years and calculated using the following 
formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
The number and percentage of subjects will be presented for age category, sex, race, and ethnicity by 
eye (OD and OS, separately).   
A subject listing that includes all demographic variables for the ITT population will be provided. 
13.2  
Pretreatment Variables 
Baseline disease characteristics captured by the Schirmers test, IOP, and VA will be summarized for all 
subjects by eye. 
 
14. Medical History and Concomitant Medications 
14.1  
Medical History 
 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment condition at the subject and event level by System Organ Class (SOC) and Preferred Term 
(PT) using the ITT population. 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.  
Listings of medical history will be generated separately for ocular and non-ocular data. 
14.2  
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary 
and summarized to the 
therapeutic drug class (Anatomical Therapeutic Chemical [ATC] 4 classification) and preferred name. If 
the ATC 4 classification is not provided, 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 


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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. 
Concomitant medications will be summarized using the ITT population by treatment-period. Ocular and 
non-ocular medications will be summarized separately.  Medications will be tabulated for each treatment 
condition 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 condition.  Listings 
of concomitant medications will be generated separately for ocular and non-ocular data. 
15. Dosing Compliance and Treatment Exposure 
15.1 
Dosing Compliance 
An Investigator will be on-site for dosing and on-call throughout the two-day duration of the study; thus, 
significant percentages of major deviations as a result of dosing compliance are not expected. 
15.2 
Treatment Exposure 
Extent of treatment exposure for subjects will be calculated in days using the following: 
Extent of Exposure (days) = Date of 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 
The presentation of extent of treatment exposure will use the safety population.  A subject listing of 
treatment exposure will also be produced that will include overall exposure.  
 
 
16. Efficacy Analyses 
16.1 
Analysis of the Primary Efficacy Endpoint(s) 
There are two primary efficacy endpoints: 1) the Schirmers test score; and 2) the conjunctival redness 
score.  The primary endpoints will be assessed using mixed model repeated measures (MMRM).  
  
  


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For any model, effects other than treatment and baseline with p values of 0.1 or greater may be removed 
optionally without consideration of convergence.  
 
 
 
 
 
 
 
   
16.2 
Analysis of the Secondary Endpoints and Secondary Analyses of Primary 
Endpoints 
The secondary endpoints are the following:  


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• 
Schirmer test responder event rate (≥ 10mm) measured before and after the final dose at visit 
2 and 4.   
• 
Conjunctival Redness measured outside the DEC for visit 2 and visit 4 at pre-dose and 10 
minutes after doses 1, 2, and 3; and  
• 
VAS for ocular dryness, discomfort, burning, grittiness and stinging, and ocular itching, 
 
 
  
Statistical models and procedures that are analogous to those used for the primary efficacy analyses 
will be employed to evaluate secondary endpoints.  
 
 
  
 
 
 
 
Secondary analyses of the primary endpoints will be repeated using the PP population.  
16.3 
Multiplicity Considerations 
P-values for the main effect of treatment will be ordered for the primary endpoints and Hochberg’s 
procedure for multiplicity control will be used. 
 
 
No type I error control will be utilized for exploratory endpoints. Thus, exploratory comparisons are 
considered hypothesis generating. 
 
17. Safety Analysis 
All safety analyses will be conducted using the safety population. 
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.  
 


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Treatment-emergent adverse events (TEAEs) are defined as any adverse event that occurs or worsens 
after the first dose of study treatment.  AEs 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 display the number of subjects who experience one or more AEs in each of the 
following categories: 
• 
All TEAEs regardless of severity or presumed relationship to Study Intervention  
• 
Treatment-Emergent AEs judged related to Study Intervention 
• 
Treatment-Emergent Severe Adverse Events  
• 
Treatment-Emergent Severe Adverse Events judged related to Study Intervention 
• 
Treatment-Emergent Serious Adverse Events  
• 
Treatment-Emergent Serious Adverse Events judged related to Study Intervention 
• 
Treatment-Emergent Adverse Events with Fatal Outcome  
• 
Treatment-Emergent Adverse Events with Fatal Outcome judged related to Study 
Intervention 
• 
Treatment-Emergent Adverse Events leading to Withdrawal from the Study  
• 
Treatment-Emergent Adverse Events leading to Withdrawal from the Study judged 
related to Study Intervention 
The number of emergent events and the number and percentage of subjects with TEAEs 
will be summarized by treatment-period. SOC and PT for different categories of TEAEs.  
At each level of tabulation (e.g., at the PT level) subjects will be counted only once if 
they had more than one such event reported during the AE collection period.  
The following summary tables will be presented for TEAE data:   
• 
Treatment-Emergent Adverse Events Overview  
• 
Treatment-Emergent Adverse Events, by Severity and Grade   
• 
Treatment-Emergent Adverse Events, by SOC and PT   
• 
Treatment-Emergent Severe Adverse Events, by SOC and PT   
• 
Treatment-Emergent Serious Adverse Events, by SOC and PT   
• 
Treatment-Emergent Adverse Events with Fatal Outcome, by SOC and PT   


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• 
Treatment-Emergent Adverse Events leading to Withdrawal from the Study, by SOC 
and PT  
• 
Treatment-Emergent Drug Related Adverse Events, by SOC and PT   
• 
Treatment-Emergent Severe Drug Related Adverse Events, by SOC and PT   
• 
Treatment-Emergent Serious Drug Related Adverse Events, by SOC and PT   
• 
Treatment-Emergent Drug Related Adverse Events with Fatal Outcome, by SOC 
and PT   
• 
Treatment-Emergent Drug Related Adverse Events leading to Withdrawal from the 
Study, by SOC and PT  
'Severe' will be defined as Grade 3 or above. A missing severity will be considered Grade 3.  
'Drug Related' will be defined as 'Definitely Related', 'Probably related' or 'Possibly Related', 
excluding 'Unlikely Related' and 'Not Related'. A missing relationship will be considered as 
'Definitely Related'.  
Separate summaries will be provided for the following categories of AEs:  
• Ocular TEAEs  
• Non-ocular TEAEs 
17.1 
Deaths, Serious Adverse Events and Other Significant Adverse Events  
17.1.1 DEATHS  
All deaths occurring up to the analysis cut-off date, regardless of causality, will be summarized 
by cause of death. 
17.1.2 SERIOUS ADVERSE EVENTS  
A listing of Serious Adverse Events (SAEs) occurring up to the analysis cut-off date will be 
provided.   
SAEs occurring before study drug initiation will be listed separately.  
17.1.3 ADVERSE EVENTS LEADING TO DISCONTINUATION OF STUDY DRUG OR WITHDRAWAL FROM STUDY  
A listing of all AEs occurring up to the analysis cut-off date and leading to discontinuation of study drug 
or withdrawal from study will be presented. 


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18. Other Safety Variables 
18.1 
Visual Acuity (ETDRS) 
The Snellen Visual Acuity (SVA) will be performed pre-DEC (and pre symptom assessment) and again 
at post-DEC exposure.  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. Subjects should use their most recent correction to attain their 
best-corrected visual acuity (BCVA). 
The observed and change from baseline visual acuity will be summarized for OD and OS, separately.  
Continuous descriptive statistics by visit for each treatment condition will be presented.  A subject listing 
of VA will also be produced.   
18.2 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, iris, lens, and lid 
will be performed pre-DEC (and pre symptom assessment) and again at post-DEC exposure. The 
results will be graded as normal, Abnormal Not Clinically Significant (NCS) or Abnormal Clinically 
Significant (CS).  Abnormal findings will be described. 
The results will be summarized using counts and percentages for each treatment condition at each visit 
for OD and OS, separately.  Percentages will be based on the number of subjects in each treatment 
condition with responses.  Shift tables for the slit-lamp biomicroscopy parameters will also be provided 
comparing each follow-up visit to baseline (Visit 1b).  A subject listing of the slit-lamp biomicroscopy 
parameters will also be produced. 
18.3 
Intraocular Pressure (IOP) 
IOP will be measured in each eye by contact tonometry by the examiner and the results will be recorded 
in mmHg.  Intraocular Pressure (IOP) will be performed prior to DEC entry.  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. 
 
The IOP values and changes from baseline for OD and OS, separately, will be summarized using 
continuous descriptive statistics by visit and eye for each treatment condition and for all actively treated 
subjects.  A subject listing of IOP also will be produced. 


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19. Additional Analyses 
Additional analyses other than the planned analyses described herein may be conducted as ad-hoc 
analyses.  All ad-hoc analyses will be identified in the CSR. The intent of any such analyses would be 
to better characterize treatment effects.  
20. Revision History 
Documentation of revision to the SAP will commence after approval of the Final version 1.0. 
21. Reporting Conventions 
The following reporting conventions will be adopted for the presentation of study data.  These 
conventions will enhance the review process and help to standardize presentation with common 
notations. 
21.1 
General Reporting Conventions 
• 
All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR. 
• 
Figures will be presented in Landscape Orientation, unless presented as part of the text 
in a CSR. 
• 
Legends will be used for all figures with more than one variable or item displayed. 
• 
Figures will be presented in color with treatment condition distinguished by different 
symbols and colors.  Lines in figures should be wide enough to view the line after being 
photocopied.  
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing.  
• 
Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as non-printable control characters, printer specific, or font specific 
characters, will not be used on a table, figure, or data listing.  Hexadecimal character 
representations are allowed (e.g.,µ,α,β). 
• 
All titles will be centered on a page.  The ICH numbering convention is to be used for 
all tables, figures, and data listings. 
• 
All footnotes will be left justified and the bottom of a page.  Footnotes must be present 
on the page where they are first referenced.  Footnotes should be used sparingly and 
must add value to the table, figure, or data listing.  If more than four footnote lines are 


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planned, then a cover page may be used to display footnotes. 
• 
Missing values for both numeric and character variables will be presented as blanks in 
a table or data listing.  A zero (0) may be used if appropriate to identify when the 
frequency of a variable is not observed. 
• 
All date values will be presented as YYYY-MM-DD (e.g., 2013-05-17) ISO 8601 format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26).  Seconds should only be reported if they were measured as 
part of the study, also in ISO 8601 format. 
• 
Time durations will be reported in mixed HHh MMm SSs notation (e.g., 5h 32m, or 27h 
52m 31s).  The use of decimal notation to present (display) time durations should be 
avoided (e.g., 0.083h = 5m) unless it is necessary to show the computation of time 
differences in a table, figure, or data listing, in which case both notations may be used 
to display the time duration.  
• 
All tables, figures, and data listings will have the Table, Listing, or Figure status (DRAFT, 
FINAL), and a date/time stamp on the bottom of each output.  
• 
All analysis programs developed for a table, figure, or data listing display will be self-
contained to facilitate transfer of programs to multiple computing environments and 
transfer to a regulatory agency (if requested).  
21.2 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly identified in the 
last title of the Table as “Population: <name of population>” and will be identical in name 
to that identified in the protocol or SAP. 
• 
Consistent terminology will be used to define and identify a population.   
• 
Sub-population(s) or special population(s) descriptions will provide sufficient detail to 
ensure comprehension of the population (e.g., FAS Females, Per-Protocol Males >60 
years of age) used for analysis in a table or figure. 
• 
Population sizes are presented for each treatment or dosing category as totals in the 
column header as (N=xxxx), where appropriate.  
• 
Population sizes with non-missing values or subset shown with summary statistics are 
represented with (n) of subjects.  


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• 
All population summaries for categorical variables will include all categories that were 
planned and for which the subjects may have had a response. Percentages 
corresponding to null categories (cells) will be suppressed.    
• 
All population summaries for continuous variables will include: N, mean, SD, minimum, 
and maximum.  Other summaries (e.g., number missing, median, quartiles, 5%, 95% 
Confidence Intervals, CV or %CV) may be used as appropriate. 
• 
All percentages are rounded and reported to xx.x%. A percentage of 100% will be 
reported as 100%.  No value of 0% will be reported.  Any computation of percent that 
results in 0% is to be presented as a blank.  
• 
Population summaries that include p-values will report the p-value to four decimal 
places with a leading zero (0.0001).  All p-values reported on default output from 
statistical software (i.e., SAS® Software version) may be reported at the default level of 
precision.  P-values <0.0001 should be reported as <0.0001 not 0.0000. 
 
22. References 
N/A