Clinical trial NCT03404115
Conditions: Dry Eye Syndrome
Keywords: reproxalap
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2018-01-02; Completion date: 2018-07-11
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Multi-Center, Phase 2b, Randomized, Double Masked, Parallel-Group, Vehicle-Controlled, Clinical Study to Assess the Safety and Efficacy of Reproxalap Ophthalmic Solution (0.25% and 0.1%) Compared to Vehicle in Subjects with Dry Eye Disease

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) intervention 2: Reproxalap Ophthalmic Solution (0.1%) intervention 3: Vehicle Ophthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) administered for approximately twelve weeks. intervention 2: Reproxalap Ophthalmic Solution (0.1%) administered for approximately twelve weeks. intervention 3: Vehicle Ophthalmic Solution administered for approximately twelve weeks.

Protocol documents:
Prot_000.pdf: 


Clinical Trial Protocol: ADX-102-DED-009 
Protocol Title: 
A Multi-Center, Phase 2b, Randomized, 
Double-Masked, Parallel-Group, Vehicle-
Controlled, Clinical Study to Assess the Safety and 
Efficacy of Reproxalap Ophthalmic Solution (0.25% 
and 0.1%) Compared to Vehicle in Subjects with 
Dry Eye Disease  
Protocol Number: 
ADX-102-DED-009 
Study Phase: 
2b 
Investigational Product Name: Reproxalap Ophthalmic Solution (0.25% and 0.1%) 
 
 
Indication: 
Dry Eye Disease (DED) 
Investigators: 
Multi-Center 
Sponsor: 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
Contract Research 
Organization: 
 
Ora. Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 USA 
 
 
 
 
 
 
 
Date 
Original Protocol: 
12 December 2017 
Amendment 1: 
{revision date} 


Reproxalap 
Aldeyra Therapeutics, Inc 
Clinical Trial Protocol: ADX-102-DED-009 
12Dec2017 Version 1.0 Final 
 
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Confidentiality Statement 
 
This protocol contains confidential, proprietary information of Ora, Inc. and/or Aldeyra 
Therapeutics, Inc.  Further dissemination, distribution or copying of this protocol or its 
contents is strictly prohibited. 
 
SPONSOR PERSONNEL 
ORA PERSONNEL 
MEDICAL MONITOR 


Reproxalap 
Aldeyra Therapeutics, Inc 
Clinical Trial Protocol: ADX-102-DED-009 
12Dec2017 Version 1.0 Final 
 
Confidential 
 
 
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SYNOPSIS 
Protocol Title: 
A Multi-Center, Phase 2b, Randomized, 
Double-Masked, Parallel-Group, Vehicle-
Controlled, Clinical Study to Assess the Safety and 
Efficacy of Reproxalap Ophthalmic Solution (0.25% 
and 0.1%) Compared to Vehicle in Subjects with 
Dry Eye Disease 
Protocol Number: 
ADX-102-DED-009 
Investigational Product: 
1) Reproxalap Ophthalmic Solution (0.25%) 
2) Reproxalap Ophthalmic Solution (0.1%) 
3) Vehicle Ophthalmic Solution  
Study Phase: 
2b 
Objective(s): 
To evaluate the efficacy of Reproxalap Ophthalmic 
Solutions (0.25% and 0.1%) on baseline to weeks 2, 
4, 8 and 12 change score
 
To evaluate effect sizes for efficacy endpoints of 
Reproxalap Ophthalmic Solutions (0.25% and 0.1%) 
vs vehicle for the treatment of the signs and 
symptoms of dry eye disease to confirm the endpoint 
selection and sample size for Phase 3 studies with 
ADX-102. 
To evaluate the safety and tolerability of Reproxalap 
Ophthalmic Solutions (0.25% and 0.1%) to vehicle 
 
 
Overall Study Design: 
Structure: 
Multi-center, double-masked, randomized study 
Duration: 
An individual subject’s participation is estimated to 
be approximately 14 weeks (98 days). 
Controls: 
Vehicle Ophthalmic Solution  
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Screening: Between Visits 1 and 2, all subjects will 
receive 14 consecutive days (± 2) of Run-in 
(vehicle) ocular drops self–administered QID in both 
eyes.  


Reproxalap 
Aldeyra Therapeutics, Inc 
Clinical Trial Protocol: ADX-102-DED-009 
12Dec2017 Version 1.0 Final 
 
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Treatment: During the 12 week (84 ± 3 days) 
treatment period, Reproxalap Ophthalmic Solution 
at concentrations of 0.1%, 0.25% or vehicle 
ophthalmic solution will be administered QID by 
bilateral topical ocular dosing. Subjects will be 
randomized to one of three treatment groups (1:1:1) 
to receive study drug after the Post–CAE® 
assessments at Visit 2. 
Summary of Visit Schedule: 
6 visits over the course of approximately 14 weeks 
• Visit 1 = Day -14 ± 2, CAE® Screening  
• Visit 2 = Day 1, CAE® Confirmation/ Baseline 
• Visit 3 = Day 15 ± 2, 2-Week Follow-Up 
• Visit 4 = Day 29 ± 2, 4-Week Follow-Up 
• Visit 5 = Day 57 ± 3, 8-Week Follow-Up 
• Visit 6 = Day 85 ± 3, 12-Week CAE® Follow-Up 
& Study Exit 
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, 
double-masked study. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 750 subjects will be screened to 
enroll approximately 300 subjects (100 per treatment 
group). 
Condition/Disease: 
Dry Eye Disease (DED) 






Reproxalap 
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Clinical Trial Protocol: ADX-102-DED-009 
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plugs during the study that have not been stable 
within 30 days of Visit 1; 
9. Be currently taking any topical ophthalmic 
prescription (including medications for 
glaucoma) or over-the-counter (OTC) solutions, 
artificial tears, gels or scrubs, and cannot 
discontinue these medications for the duration of 
the trial (excluding medications allowed for the 
conduct of the study); 
10. Have corrected visual acuity greater than or 
equal to logarithm of the minimum angle of 
resolution (logMAR) + 0.7 as assessed by Early 
Treatment of Diabetic Retinopathy Study 
(ETDRS) scale in both eyes at Visit 1; 
11. Be a woman who is pregnant, nursing, or 
planning a pregnancy; 
12. Be unwilling to submit a urine pregnancy test at 
Visit 1 and Visit 6 (or early termination visit) if 
of childbearing potential.  Non-childbearing 
potential is defined as a woman who is 
permanently sterilized (e.g., has had a 
hysterectomy or tubal ligation), or is post-
menopausal (without menses for 12 consecutive 
months); 
13. Be a man or woman of childbearing potential 
who is not using an acceptable means of birth 
control; acceptable methods of contraception 
include: hormonal – oral, implantable, 
injectable, or transdermal contraceptives; 
mechanical – spermicide in conjunction with a 
barrier such as a diaphragm or condom; 
intrauterine device (IUD); or surgical 
sterilization of partner.  For non-sexually active 
males or females, abstinence may be regarded as 
an adequate method of birth control; however, if 
the subject becomes sexually active during the 
study, he/she must agree to use adequate birth 
control as defined above for the remainder of the 
study; 
14. Have a known allergy and/or sensitivity to the 






Reproxalap 
Aldeyra Therapeutics, Inc 
Clinical Trial Protocol: ADX-102-DED-009 
12Dec2017 Version 1.0 Final 
 
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TABLE OF CONTENTS 
SYNOPSIS ................................................................................................................. 3
TABLE OF CONTENTS ......................................................................................... 10
LIST OF ABBREVIATIONS ........................................................................................... 13
1
INTRODUCTION .................................................................................................... 15
2
Clinical Studies of Reproxalap Ophthalmic Solution .............................................. 16
2.1
Minimization of Risk ..................................................................................... 19
3
STUDY OBJECTIVES ............................................................................................ 19
4
CLINICAL HYPOTHESES ..................................................................................... 19
5
OVERALL STUDY DESIGN ................................................................................. 20
6
STUDY POPULATION ........................................................................................... 21
Number of Subjects (approximate) ................................................................ 21
6.1
Study Population Characteristics ................................................................... 21
6.2
Inclusion Criteria ............................................................................................ 22
6.3
Exclusion Criteria .......................................................................................... 22
6.4
Withdrawal Criteria (if applicable) ................................................................ 24
6.5
7
STUDY PARAMETERS ......................................................................................... 24
Efficacy Measures and Endpoints .................................................................. 24
7.1
7.1.1
Efficacy Measure(s) .......................................................................... 24
7.1.2
Efficacy Endpoint(s) ......................................................................... 24
7.1.3
Criteria for Effectiveness .................................................................. 24
Safety Measures ............................................................................................. 25
7.2
8
STUDY MATERIALS ............................................................................................. 25
Study Treatment(s) ......................................................................................... 25
8.1
8.1.1
Study Treatment(s)/ Formulation(s) ................................................. 25
8.1.2
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s). ....................... 25
8.1.3
Instructions for Use and Administration .......................................... 25
Other Study Supplies ..................................................................................... 26
8.2
9
STUDY METHODS AND PROCEDURES ............................................................ 26
Subject Entry Procedures ............................................................................... 26
9.1
9.1.1
Overview .......................................................................................... 26
9.1.2
Informed Consent ............................................................................. 26
9.1.3
Washout Intervals ............................................................................. 26
9.1.4
Procedures for Final Study Entry ..................................................... 26
9.1.5
Methods for Assignment to Treatment Groups: ............................... 26
Concurrent Therapies ..................................................................................... 27
9.2
9.2.1
Prohibited Medications/Treatments .................................................. 27
9.2.2
Escape Medications .......................................................................... 27
9.2.3
Special Diet or Activities .................................................................. 27
Examination Procedures ................................................................................ 27
9.3
9.3.1
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................ 27
9.3.2
Visit 1: Day –14 ± 2 – CAE® Screening .......................................... 27
9.3.3
Visit 2:  Day 1 – CAE® Confirmation and Baseline ........................ 29


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9.3.4
Visit 3 (Day 15 ±2) ........................................................................... 30
9.3.5
Visit 4: Day 29 ± 2 ........................................................................... 31
9.3.6
Visit 5: Day 57 ± 3 ........................................................................... 31
9.3.7
Visit 6: Day 85 ± 3 ........................................................................... 32
Schedule of Visits, Measurements and Dosing .............................................. 33
9.4
9.4.1
Scheduled Visits ............................................................................... 33
9.4.2
Unscheduled Visits ........................................................................... 33
Compliance with Protocol .............................................................................. 34
9.5
Subject Disposition ........................................................................................ 34
9.6
9.6.1
Completed Subjects .......................................................................... 34
9.6.2
Discontinued Subjects ...................................................................... 34
Study Termination .......................................................................................... 35
9.7
Study Duration ............................................................................................... 35
9.8
Monitoring and Quality Assurance ................................................................ 35
9.9
10
ADVERSE EVENTS ............................................................................................... 35
Adverse Event ................................................................................................ 35
10.1
10.1.1
Severity ............................................................................................. 36
10.1.2
Relationship to Investigational Product ............................................ 36
10.1.3
Expectedness .................................................................................... 36
Serious Adverse Events ................................................................................. 37
10.2
Procedures for Reporting Adverse Events ..................................................... 37
10.3
10.3.1
Reporting a Suspected Unexpected Adverse Reaction ..................... 38
10.3.2
Reporting a Serious Adverse Event .................................................. 38
Procedures for Unmasking (if applicable) ..................................................... 38
10.4
Type and Duration of the Follow-up of Subjects after Adverse Events ........ 39
10.5
11
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .................... 39
Analysis Populations ...................................................................................... 39
11.1
Statistical Hypotheses .................................................................................... 40
11.2
Sample Size .................................................................................................... 40
11.3
Statistical Analysis ......................................................................................... 41
11.4
11.4.1
General Considerations .................................................................... 41
11.4.2
Unit of Analysis ................................................................................ 41
11.4.3
Missing Data ..................................................................................... 41
11.4.4
Multiplicity Consideration ................................................................ 41
11.4.5
Efficacy Analyses ............................................................................. 42
11.4.6
Safety Variables ................................................................................ 42
11.4.7
Interim Analyses ............................................................................... 42
12
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................... 43
Protection of Human Subjects ........................................................................ 43
12.1
12.1.1
Subject Informed Consent ................................................................ 43
12.1.2
Institutional Review Board (IRB) Approval .................................... 43
Ethical Conduct of the Study ......................................................................... 43
12.2
Subject Confidentiality .................................................................................. 43
12.3
Documentation ............................................................................................... 44
12.4
12.4.1
Retention of Documentation ............................................................. 44


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Clinical Trial Protocol: ADX-102-DED-009 
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Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
12.5
Investigational Product .................................................................................. 44
12.5.1
Labeling/Packaging .......................................................................... 44
12.5.2
Storage of Investigational Product ................................................... 45
12.5.3
Accountability of Investigational Product ........................................ 45
12.5.4
Return or Disposal of Investigational Product ................................. 45
Recording of Data on Source Documents and Case Reports Forms (CRFs) . 45
12.6
Publications .................................................................................................... 46
12.7
13
REFERENCES ......................................................................................................... 47
14
APPENDICES .......................................................................................................... 49
Appendix 1: Schedule of Visits and Measurements .......................................................... 49
Appendix 2: Examination Procedures, Tests, & Evaluations ............................................ 50
Appendix 3: Protocol Amendment Summary ................................................................... 62
Appendix 4: Sponsor and Ora Approvals .......................................................................... 63
Appendix 5: Investigator’s Signature ................................................................................ 64
 
 
 
 
 


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Clinical Trial Protocol: ADX-102-DED-009 
12Dec2017 Version 1.0 Final 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
API 
active pharmaceutical ingredient 
BCVA 
best-corrected visual acuity 
CAE 
controlled adverse environment 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CPT 
Current Procedural Terminology 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CV 
coefficient of variation 
DED 
dry eye disease 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IM 
intramuscular 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
KCS 
keratoconjunctivitis sicca 
LASIK 
laser in situ keratomileusis 
LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 


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Clinical Trial Protocol: ADX-102-DED-009 
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ND  
not done  
NDA 
new drug application 
NF 
national formulary 
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
 
 
OU 
both eyes 
OTC 
over the counter 
PE 
polyethylene 
PHI 
protected health information 
PO 
by mouth 
PP 
per protocol 
PRN 
as needed 
QD 
once daily 
QID 
Four times daily 
QS 
as much as will suffice 
ROPI 
Report of Prior Investigations  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
 
 
SOP 
standard operating procedure 
TF 
tear film 
 
 
Tmax 
time of maximum concentration 
USP 
United States Pharmacopeia 
VA 
visual acuity 
w/v 
weight per unit volume 
 
 


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Clinical Trial Protocol: ADX-102-DED-009 
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1 INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                               
 
 


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• 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
2 Clinical Studies of Reproxalap Ophthalmic Solution 
Reproxalap topical ocular solution is being developed for ocular inflammation.  
 
 
 
 
  




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Clinical Trial Protocol: ADX-102-DED-009 
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Table 2. 
Topical Ocular Reproxalap Clinical Trial Outcomes 
Clinical Trial 
Indication 
Summary Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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2.1 
Minimization of Risk 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
3 STUDY OBJECTIVES 
The study objectives are as stated below: 
• To evaluate the efficacy of Reproxalap Ophthalmic Solutions (0.25% and 0.1%) 
on baseline to weeks 2, 4, 8 and 12 change scores 
 
 
• To evaluate effect sizes for efficacy endpoints of Reproxalap Ophthalmic 
Solutions (0.25% and 0.1%) versus vehicle for the treatment of the signs and 
symptoms of dry eye disease to confirm the endpoint selection and sample size 
for Phase 3 studies with ADX-102. 
• To evaluate the safety and tolerability of Reproxalap Ophthalmic Solutions 
(0.25% and 0.1%) to vehicle 
 
 
4 CLINICAL HYPOTHESES 
The clinical hypotheses for this study are that 0.10% and/or 0.25% Reproxalap 
Ophthalmic Solution is superior to vehicle
 
 








Reproxalap 
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Clinical Trial Protocol: ADX-102-DED-009 
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1. Have any clinically significant slit lamp findings at Visit 1 that may include active 
blepharitis, meibomian gland dysfunction (MGD), lid margin inflammation, or active 
ocular allergies that require therapeutic treatment, and/or in the opinion of the 
investigator may interfere with study parameters; 
2. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), or active 
ocular inflammation at Visit 1; 
3. Have worn contact lenses within 7 days of Visit 1 or anticipate using contact lenses 
during the study; 
4. Have used any eye drops within 2 hours of Visit 1; 
5. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within the 
last 12 months; 
6. Have used cyclosporine 0.05% or lifitigrast 5.0% ophthalmic solution within 90 days 
of Visit 1; 
7. Have any planned ocular and/or lid surgeries over the study period or any ocular 
surgery within 6 months of Visit 1; 
8. Be using or anticipate using temporary punctal plugs during the study that have not 
been stable within 30 days of Visit 1; 
9. Be currently taking any topical ophthalmic prescription (including medications for 
glaucoma) or over-the-counter (OTC) solutions, artificial tears, gels or scrubs, and 
cannot discontinue these medications for the duration of the trial (excluding 
medications allowed for the conduct of the study); 
10. Have corrected visual acuity greater than or equal to logarithm of the minimum angle 
of resolution (logMAR) + 0.7 as assessed by Early Treatment of Diabetic 
Retinopathy Study (ETDRS) scale in both eyes at Visit 1; 
11. Be a woman who is pregnant, nursing, or planning a pregnancy; 
12. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 6 (or early 
termination visit) if of childbearing potential.  Non-childbearing potential is defined 
as a woman who is permanently sterilized (e.g., has had a hysterectomy or tubal 
ligation), or is post-menopausal (without menses for 12 consecutive months); 
13. Be a man or woman of childbearing potential who is not using an acceptable means 
of birth control; acceptable methods of contraception include: hormonal – oral, 
implantable, injectable, or transdermal contraceptives; mechanical – spermicide in 
conjunction with a barrier such as a diaphragm or condom; intrauterine device (IUD); 
or surgical sterilization of partner.  For non-sexually active males or females, 
abstinence may be regarded as an adequate method of birth control; however, if the 
subject becomes sexually active during the study, he/she must agree to use adequate 
birth control as defined above for the remainder of the study; 
14. Have a known allergy and/or sensitivity to the test article or its components; 
15. Have a condition or be in a situation which the investigator feels may put the subject 
at significant risk, may confound the study results, or may interfere significantly with 
the subject’s participation in the study; 
16. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days of Visit 1; 


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Clinical Trial Protocol: ADX-102-DED-009 
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17. Have previously used reproxalap ophthalmic solution; 
18. Be currently using any medication known to cause ocular drying that is not used on a 
stable dosing regimen for at least 30 days prior to Visit 1; 
19. Be unable or unwilling to follow instructions, including participation in all study 
assessments and visits. 
 Withdrawal Criteria (if applicable) 
6.5
If at any time during the study the investigator determines that a subject’s safety has 
been compromised, the subject may be withdrawn from the study. 
Subjects may withdraw consent from the study at any time. 
Sponsor and/or investigator may discontinue any subject for non-compliance or any 
valid medical reason (see Section 9.6.2). 
7 STUDY PARAMETERS 
 Efficacy Measures and Endpoints 
7.1
7.1.1 Efficacy Measure(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Questionnaire 
• Ocular Surface Disease Index (OSDI)© 
 
 
 
 
7.1.2 Efficacy Endpoint(s) 
The efficacy endpoints are changes from baseline at weeks 2, 4, 8 and 12 for each 
efficacy measure, where available.  Endpoints will be calculated pre-CAE and, where 
available post-CAE and as pre- to post-CAE changes.    
7.1.3 Criteria for Effectiveness 
Success would be demonstrating statistically significant (p<0.05) effects on at least one 
DED sign or at least one DED symptom at week 12 


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Clinical Trial Protocol: ADX-102-DED-009 
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 Safety Measures 
7.2
• Visual acuity (ETDRS); 
• Slit-lamp biomicroscopy; 
• Adverse event query; 
• Dilated Fundoscopy;  
• Intraocular Pressure; 
8 STUDY MATERIALS 
 Study Treatment(s) 
8.1
8.1.1 Study Treatment(s)/ Formulation(s) 
• Reproxalap Ophthalmic Solution (0.25%) 
• Reproxalap Ophthalmic Solution (0.10%) 
• Vehicle Ophthalmic Solution 
8.1.2 Description of and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period(s). 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. 
The dosage and dosage regimen was selected based on nonclinical and clinical studies 
described in Section 2.
 
 
8.1.3 Instructions for Use and Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Other Study Supplies 
8.2
 
9 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
9.1
9.1.1 Overview 
Subjects as defined by the criteria in sections 6.2, 6.3, and 6.4 will be considered for entry 
into this study. 
9.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed 
consent form.  The informed consent form must be the most recent version that has 
received approval/favorable review by a properly constituted Institutional Review Board 
(IRB). 
9.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the exclusion criteria 
(Section 6.4). 
9.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria. 
9.1.5 Methods for Assignment to Treatment Groups: 
Before the initiation of study run-in at Visit 1, each subject who provides written and 
informed consent will be assigned to a screening number. All screening numbers will be 
assingned in strict numerical sequence at a site and no numbers will skipped or omitted. 
Each subject who meets all the inclusion and none of the exclusion criteria at Visit 1 and 
Visit 2 will be assigned a randomization number at the end of Visit 2. The Interactive 
Web Response System (IWRS) will be used to assign all randomization numbers. 
Randomization and kit numbers will be assigned automatically to each subject as they are 
entered into the IWRS.  
The site staff will dispense kit(s) required until the next visit. Both the randomization 
number and the dispensed study drug kit number(s) will be recorded on the subject’s 
















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• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator. 
 Compliance with Protocol 
9.5
Subjects will be instructed on proper use of the subject daily diary and proper instillation 
and storage of study drug at the end of Visits 1, 2, 3, 4 and 5, and given written 
instructions. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 Subject Disposition 
9.6
9.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
9.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• 
subject request/withdrawal 
• 
AEs 
• 
protocol violations 
• 
administrative reasons (e.g., inability to continue, lost to follow up) 
• 
sponsor termination of study 
• 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or sponsor and will be clearly documented on the eCRF. 


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Clinical Trial Protocol: ADX-102-DED-009 
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 Study Termination 
9.7
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
 Study Duration 
9.8
An individual subject’s participation will involve 6 visits over approximately a 14-week 
(~98 days) period (84 days of treatment and 14 days pre-screening). 
 Monitoring and Quality Assurance 
9.9
During the course of the study an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, and ensure the study is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring 
plan. 
Regulatory authorities of domestic and foreign agencies, quality assurance and or its 
designees may carry out on-site inspections and/or audits which may include source data 
checks. Therefore direct access to the original source data will be required for inspections 
and/or audits. All inspections and audits will be carried out giving consideration to data 
protection as well as subject confidentiality to the extent that local, state, and federal laws 
apply. 
10 ADVERSE EVENTS 
 Adverse Event 
10.1
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
from any use of the IP (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the CRF. Any clinically relevant deterioration in clinical finding is considered 


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an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning. 
Exacerbation of conditions related to the signs and symptoms of Dry Eye will not be 
reported as an AE. 
10.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
 
 
 
 
 
 
 
 
 
10.1.2 Relationship to Investigational Product 
The Investigator must assess whether they consider an AE to be drug-related.  In 
assessing this relationship, the Investigator must use information about the 
conditions/concurrent medication, and chronology of the event relative to drug 
administration.  The following definitions will be used:  
§ Definitely Related 
§ Probably Related 
§ Possibly Related 
§ Unlikely to be related 
§ Not Related 
10.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
§ Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
§ Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
§ Not applicable: An AE unrelated to the IP. 


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AE events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
 Serious Adverse Events 
10.2
An AE is considered serious if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
§ Death; 
§ A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the subject at immediate risk of death. It does not include 
an AE that, had it occurred in a more severe form, might have caused death. 
§ Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if less 
than 24 hours). For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does 
not include: emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
§ A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
§ A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 Procedures for Reporting Adverse Events 
10.3
All AEs and their outcomes must be reported to Ora, the sponsor, and the IRB/IEC as 
required by the IRB/IEC, federal, state, or local regulations and governing health 




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notified before unmasking study drug. Ora and/or the study sponsor must be informed 
immediately about any unmasking event. 
If an investigator identifies a medical need for unmasking the treatment assignment of a 
subject, he/she should contact Ora and/or the medical monitor prior to unmasking the 
identity of the IP, if possible. Ora will ask the site to complete and send them the 
Unmasking Request Form. Ora will notify Aldeyra and jointly will determine if the 
unmasking request should be granted. They may consult the medical monitor as needed. 
The result of the request will be documented on the Unmasking Request Form. If 
approval is granted to unmask a subject, written permission via the Unmasking Request 
Form will be provided to the investigator. The investigator will unmask the subject using 
IWRS. The investigator will complete the Unmasking Memo form and include it in the 
subject’s study file and provide a copy for the TMF. For each unmasked request, the 
reason, date, signature, and name of the person who unmasked the subject, must be noted 
in the subject’s study file.  
Unmasked subjects will be discontinued from the study. 
 Type and Duration of the Follow-up of Subjects after Adverse 
10.5
Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the AE. If the subject is lost to follow-up, the investigator 
should make 3 reasonable attempts to contact the subject via telephone, post, or certified 
mail. All follow-up will be documented in the subject’s source document. Non-serious 
AEs identified on the last scheduled contact must be recorded on the AE eCRF with the 
status noted.  
If the investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora within 24 hours of the site’s awareness of the 
new information. The original SAE form is not to be altered. The report should describe 
whether the event has resolved or continues and how the event was treated. 
11 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 Analysis Populations 
11.1
The following analysis populations will be considered: 
• Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as 
randomized. 
 








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12 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonisation (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be adhered to. 
 Protection of Human Subjects 
12.1
12.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each subject 
and/or from the subject’s parent or legal guardian prior to enrollment into the study. If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB prior to their use. If the consent form requires 
revision (e.g., due to a protocol amendment or significant new safety information), it is 
the investigator’s responsibility to ensure that the amended informed consent is reviewed 
and approved by Ora prior to submission to the governing IRB and that it is read, signed 
and dated by all subjects subsequently enrolled in the study as well as those currently 
enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and/or sponsor and provided in 
writing by Ora and/or sponsor prior to the consent process. 
12.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The investigator must obtain appropriate IRB approval before initiating the 
study and re-approval at least annually. 
Only an IRB approved version of the informed consent form will be used. 
 Ethical Conduct of the Study 
12.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
12.3
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 


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ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB/IEC 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the subject’s original 
medical and study records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to the aforementioned individuals to the 
extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
12.4
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and EKGs. The investigator’s copy of the CRFs serves as the 
investigator’s record of a subject’s study-related data. 
12.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of CRFs should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region; or until at 
least two years have elapsed since the formal discontinuation of clinical development of 
the IP. These documents will be retained for a longer period if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
 Labeling, Packaging, Storage, Accountability, and Return or 
12.5
Disposal of Investigational Product 
12.5.1 Labeling/Packaging 
Investigational drug will be packaged and labeled into clinical kits. 
 
  


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12.5.2 Storage of Investigational Product 
 
 
 
12.5.3 Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or his/her named sub-
investigator(s), and is to only be used in accordance with this protocol. The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study. A detailed inventory must be completed for the IP. 
12.5.4 Return or Disposal of Investigational Product 
All IP will be returned to the sponsor or their designee or destroyed at the study site. The 
return or disposal of IP will be specified in writing. 
 Recording of Data on Source Documents and Case Reports Forms 
12.6
(CRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
Data entry of all enrolled and randomized subjects will use software that conforms to 21 
CFR Part 11 requirements, and will be performed only by staff who have been trained on 
the system and have access to the system. Data will not be entered for screen failure 
subjects. An audit trail will be maintained within the electronic system to capture all 
changes made within the eCRF database. After the end of the study and database lock, 
compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be provided 
to each Investigator Site to be maintained on file by the Investigator. 


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 Publications 
12.7
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript
 
 
 
 


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13 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, & 
EVALUATIONS  


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APPENDIX 3: PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 


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APPENDIX 4: SPONSOR AND ORA APPROVALS 
Protocol Title: 
A Multi-Center, Phase 2b, Randomized, Double 
Masked, Parallel-Group, Vehicle-Controlled, Clinical 
Study to Assess the Safety and Efficacy of 
Reproxalap  Ophthalmic Solution (0.25% and 0.1%) 
Compared to Vehicle in Subjects with Dry Eye 
Disease 
Protocol Number: ADX-102-DED-009 
Final Date:  
12 December 2017 
This clinical study protocol was subject to critical review and has been approved by the sponsor.  
The following personnel contributed to writing and/or approving this protocol. 


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APPENDIX 5: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Multi-Center, Phase 2b, Randomized, Double 
Masked, Parallel-Group, Vehicle-Controlled, Clinical 
Study to Assess the Safety and Efficacy of 
Reproxalap  Ophthalmic Solution (0.25% and 0.1%) 
Compared to Vehicle in Subjects with Dry Eye 
Disease 
Protocol Number: ADX-102-DED-009 
Final Date:  
12 December 2017 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations.  I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
A Multi-Center, Phase 2b, Randomized, Double-Masked, Parallel-
Group, Vehicle-Controlled, Clinical Trial to Assess the Safety and 
Efficacy of Reproxalap Ophthalmic Solution (0.25% and 0.1%) 
Compared to Vehicle in Subjects with Dry Eye Disease 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
 
 
 
Protocol Number: 
ADX-102-DED-009 
 
 
Author:   
 
 
 
 
 
 
 
 
Date:    
 
30-July-2018 
Version:  
 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 




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


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13. 
Efficacy Analyses ................................................................................................................... 17 
13.1 Lissamine Green Staining ...................................................................................................... 18 
13.2 Fluorescein Staining .............................................................................................................. 19 
13.3 Tear Film Break-Up Time (TFBUT)........................................................................................ 20 
13.4 Unanesthetized Schirmer’s Test ............................................................................................ 20 
13.5 Ora Calibra® Ocular Discomfort Scale ................................................................................... 21 
13.5.1 
Ora Calibra® Ocular Discomfort Scale Pre-, Post-, and Non-CAE® ........................... 21 
13.5.2 
Ora Calibra® Ocular Discomfort Scale During CAE® Exposure ................................. 21 
13.6 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire .............................................. 22 
13.6.1 
Assessments During Visits ........................................................................................ 22 
13.6.2 
Diary Assessments .................................................................................................... 22 
13.7 Ocular Surface Disease Index© ............................................................................................. 23 
13.8 SANDE Questionnaire ........................................................................................................... 23 
13.9 Tear Osmolarity ..................................................................................................................... 24 
14. 
Safety Analyses ..................................................................................................................... 24 
14.1 Adverse Events ...................................................................................................................... 24 
14.2 Visual Acuity (ETDRS) ........................................................................................................... 26 
14.3 Slit-Lamp Biomicroscopy Examination .................................................................................. 26 
14.4 Dilated Fundoscopy Examination .......................................................................................... 27 
14.5 Intraocular Pressure (IOP) ..................................................................................................... 27 
15. 
Interim Analyses .................................................................................................................... 27 
16. 
Optimization Analyses ........................................................................................................... 28 
17. 
Changes from Protocol-Stated Analyses ............................................................................... 28 
18. 
Additional Analyses ................................................................................................................ 29 
19. 
Revision History ..................................................................................................................... 29 
20. 
Tables .................................................................................................................................... 29 
21. 
Listings ................................................................................................................................... 44 
22. 
Figures ................................................................................................................................... 46 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCVA 
Best Corrected Visual Acuity 
CAE 
Controlled Adverse Environment 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
ESWE 
Endpoint-Specific Worst Eye 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
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 
SDC 
Statistics and Data Corporation, Incorporated 
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 planned analyses and reporting for 
protocol ADX-102-DED-009, version 1.0 dated 12Dec2017. 
This SAP is being 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). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  In keeping with the preliminary nature of a Phase 2 
study, additional analyses other than the planned analyses described herein may be conducted as ad-
hoc analyses and will be identified in the CSR.  The intent of any such analyses would be to better 
characterize treatment effects and improve the design of a future Phase 3 study. 
2. Study Objectives 
The study objectives are as stated below: 
• 
 
 
 
 
 
 
 
 
 
2.1 Study Variables 
In this Phase 2b study there are no primary or secondary endpoints.  All endpoints are considered 
hypothesis-generating and not hypothesis-testing.  Efficacy variables and safety variables follow. 
2.2 Efficacy Variables 
The efficacy variables include the following: 
• 
 
 
 
 
 
 
 


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• 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 
 
 
 
 
 
2.3 Safety Variables 
The safety variables include the following: 
• 
Visual acuity (VA) (ETDRS [Early Treatment of Diabetic Retinopathy Study]) 
• 
Slit-lamp biomicroscopy 
• 
Adverse event (AE) query 
• 
Dilated Fundoscopy 
• 
Intraocular Pressure (IOP) 
2.4 Statistical Hypotheses 
The following hypotheses will be tested for each dose of reproxalap, each dry eye disease (DED) sign 
and symptom, 
 
  
 
   
 
   
 
   
 
   
3. Study Design and Procedures 
3.1 General Study Design 
This is a Phase 2b, multicenter, randomized, double–masked, vehicle-controlled, parallel-group design 
with block enrollment.  Approximately 300 subjects will be randomly assigned to one of the three 




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3.2 Schedule of Visits and Assessments 
The schedule of visits and assessments is provided below. 




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6. Data Preparation 
Electronic Case Report Forms (eCRF) will be developed by Statistics and Data Corporation, 
Incorporated (SDC) following SDTM standards unless otherwise specified by Aldeyra Therapeutics, Inc.  
Data from source documents will be entered into the eCRF by site personnel.  All users will complete 
role-based system and study-specific eCRF training prior to receiving access to the study database. 
User access will be granted based on a user’s role in the study and will be controlled through individual 
login credentials including a unique User ID and password. 
The clinical study database will be developed and tested in 
 delivered as a 
single-instance multi-tenant Software-as-a-Service (SaaS) EDC system and is developed, maintained, 
and hosted by 
. Therefore, over the duration of the 
study, 
 may apply system updates to the EDC system as part of their continuous 
improvement efforts.  
After data are entered into the clinical study database, electronic edit checks and data review will be 
performed.  All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document.  When the database has been declared to be complete and accurate, the 
database will be locked.  Any changes to the database after data have been locked can only be made 
with the approval of Aldeyra Therapeutics, Inc. and Ora, Inc. in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
 
 
 
 
 
  
 
 
 
. 
7. Analysis Populations 
Analysis populations include 
 
 
 
. 






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8.5 Adjustments for Multiplicity 
As this is a Phase 2b study, there will be no multiplicity adjustments for the two active treatments or for 
the multiple endpoints. 
9. Disposition of Subjects 
Subject disposition will be presented 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 Concomitant Medications 
Concomitant medications will be coded 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
  Listings of concomitant 
medications will be generated separately for ocular and non-ocular data. 
12. Dosing Compliance and Treatment Exposure 
12.1 Dosing Compliance 
Subjects will be instructed on proper use of the subject daily diary and proper instillation and storage of 
study drug 
 
 
 
 
 
  
 
 


















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An overall summary will be presented that includes the number of AEs, TEAEs, serious AEs (SAE), and 
serious TEAEs (TE-SAE).  The summary will also include the number and percentage of subjects 
withdrawn due to an AE, the number and percentage of subjects with an AE resulting in death, and the 
number and percentage of subjects who experienced at least one AE, TEAE, SAE and TE-SAE, by 
treatment group and for all subjects.  This summary will include breakdowns of AEs further categorized 
as ocular or non-ocular. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE.  These summaries will be presented by SOC and PT.  Non-ocular 
TEAEs will be summarized using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT.  Ocular TEAEs 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.  In the summary, SOC will be listed in order of descending 
frequency for all subjects; PTs will be listed in order of descending frequency for all subjects within each 
SOC.  The occurrence of non-ocular and ocular TEAEs will also be tabulated by SOC, PT, and maximal 
severity, and by SOC, PT, and study day of onset. 
Separate summaries will be provided for the following categories of AEs:  
• 
Ocular TEAEs  
• 
Non-ocular TEAEs  
• 
Treatment-related TEAEs 
• 
SAEs 
Severity of an AE  is defined as a qualitative assessment of the degree of intensity of an adverse event 
as determined by the investigator or reported to him/her by the patient/subject.  The assessment of 
severity is made irrespective of relationship to study drug or seriousness of the event and should be 
evaluated according to the following scale: 
• 
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities. 
• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with 
the subject’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
Summaries of TEAEs by maximal severity will be presented for ocular AEs and non-ocular AEs 
separately.  The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC 


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and PT within each SOC by treatment group.  To count the number of subjects with any TEAEs, if a 
subject has multiple TEAEs coded to the same PT within the same SOC, the subject will be counted 
once under the maximal severity. 
The relationship of each adverse event to the investigational product should be determined by the 
investigator (in a blinded manner) using these descriptions: 
• 
Definitely Related 
• 
Probably Related 
• 
Possibly Related 
• 
Unlikely to be Related 
• 
Not Related 
Definitely related, probably related, and possibly related TEAEs will be considered as treatment-
related TEAEs.  Any TEAEs with missing relationships will also be considered as treatment-related.  
All AEs will be presented in a subject listing that classifies each AE as ocular or non-ocular and indicates 
whether it is a TEAE.  Separate listings will be produced for AEs leading to study discontinuation,  AEs 
leading to death and SAEs. 
14.2 Visual Acuity (ETDRS) 
The VA procedure will be performed 
 
 
 
 
 
 
 
  A subject listing of 
VA will also be produced.   
14.3 Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination o
 
will be performed 
 
 
 
 




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16. Optimization Analyses 
Upon completion of this study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
    
17. Changes from Protocol-Stated Analyses