Clinical trial NCT03494504
Conditions: Allergic Conjunctivitis
Keywords: reproxalap
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2018-03-30; Completion date: 2018-11-05
Enrollment: 318 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Multi-Center, Double-Masked, Randomized, Parallel-Group, Vehicle-Controlled, Clinical Trial to Assess the Safety and Efficacy of Reproxalap Ophthalmic Solutions in Subjects with Acute Allergic Conjunctivitis

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 (0.5%) intervention 3: Vehicle Ophthalmic Solution
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) administered once. intervention 2: Reproxalap Ophthalmic Solution (0.5%) administered once. intervention 3: Vehicle Ophthalmic Solution administered once.

Protocol documents:
Prot_000.pdf: 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
CONFIDENTIAL 
Page 1 of 58 
CLINICAL TRIAL PROTOCOL: ADX-102-AC-008 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Parallel-Group, Vehicle-Controlled, Phase 3 
Clinical Trial to Assess the Safety and Efficacy of 
Reproxalap Ophthalmic Solutions (0.25% and 
0.5%) Compared to Vehicle in the Conjunctival 
Allergen Challenge (Ora-CAC®) Model of Acute 
Allergic Conjunctivitis  
Protocol Number: 
ADX-102-AC-008 
Name of Test Drug 
/Investigational Product: 
Reproxalap Ophthalmic Solution (0.25% and 0.5%) 
IND/IDE/PMA Number: 
 
Indication Studied: 
Acute allergic conjunctivitis 
Development Phase: 
3 
Brief Description: 
Multi-center, double-masked, randomized, parallel-
group, vehicle-controlled, phase 3 CAC trial. 
Name of Sponsor: 
 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
Contract Research 
Organization: 
 
Ora, Inc. 
300 Brickstone Square, Third Floor 
Andover, MA 01810 USA 
IRB/IEC: 
 
 
 
 
 
Date 
Original Protocol: 
15 February 2018 
 
 
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. 


Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
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SPONSOR (Aldeyra) PERSONNEL 
Chief Medical Officer: 
 
  
ORA PERSONNEL 
Chief Medical Officer: 
 
 
 
Department Vice President: 
 
 
 
Project Lead: 
 
 
 
MEDICAL MONITOR 
Medical Monitor: 
  
 
 
 
 
 
 
 
 
 
 














Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL: ADX-102-AC-008 ...................................................1 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ..................................................................................................9 
List of Abbreviations .......................................................................................................12 
1 INTRODUCTION......................................................................................................14 
2 STUDY OBJECTIVES ..............................................................................................16 
3 CLINICAL HYPOTHESES .....................................................................................16 
4 OVERALL STUDY DESIGN ...................................................................................17 
5 STUDY POPULATION ............................................................................................17 
 
Number of Subjects (approximate) ..................................................................17 
5.1
 
Study Population Characteristics .....................................................................17 
5.2
 
inclusion Criteria ................................................................................................17 
5.3
 
Exclusion Criteria ..............................................................................................18 
5.4
 
Withdrawal Criteria (if applicable) ..................................................................19 
5.5
6 STUDY MEASURES .................................................................................................20 
 
Efficacy Measures ..............................................................................................20 
6.1
 Primary Efficacy Endpoint(s) .........................................................................20 
6.1.1
 Key Secondary Efficacy Endpoint .................................................................20 
6.1.2
 Additional Secondary Efficacy Endpoint(s) ...................................................20 
6.1.3
 
Safety Measures ..................................................................................................20 
6.2
7 STUDY MATERIALS ...............................................................................................21 
 
Study Treatment(s) ............................................................................................21 
7.1
 Study Treatment(s)/ Formulation(s) ...............................................................21 
7.1.1
 Instructions for Use and Administration ........................................................21 
7.1.2
 
Other Study Supplies .........................................................................................21 
7.2
8 STUDY METHODS AND PROCEDURES ............................................................22 
 
Subject Entry Procedures ..................................................................................22 
8.1
 Overview ........................................................................................................22 
8.1.1
 Informed Consent ...........................................................................................22 
8.1.2
 Washout Intervals ...........................................................................................22 
8.1.3
 Procedures for Final Study Entry ...................................................................23 
8.1.4
 Methods for Assignment to Treatment Groups: .............................................23 
8.1.5
 
Concurrent Therapies ........................................................................................23 
8.2
 Prohibited Medications/Treatments ...............................................................24 
8.2.1
 Escape Medications ........................................................................................24 
8.2.2
 Special Diet or Activities ...............................................................................24 
8.2.3
 
Examination Procedures....................................................................................24 
8.3
 Procedures to be Performed at Each Study Visit with Regard to Study 
8.3.1
Objective(s) ....................................................................................................25 
 
Schedule of Visits, Measurements and Dosing ................................................29 
8.4
 Scheduled Visits .............................................................................................29 
8.4.1
 Unscheduled Visits .........................................................................................29 
8.4.2


Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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Compliance with Protocol .................................................................................30 
8.5
 
Subject Disposition .............................................................................................30 
8.6
 Completed Subjects ........................................................................................30 
8.6.1
 Discontinued Subjects ....................................................................................30 
8.6.2
 
Study Termination .............................................................................................31 
8.7
 
STUDY DURATION .........................................................................................31 
8.8
 
Monitoring and Quality Assurance ..................................................................31 
8.9
9 ADVERSE EVENTS .................................................................................................31 
 Severity ...........................................................................................................32 
9.1.1
 Relationship to Investigational Product .........................................................32 
9.1.2
 Expectedness ..................................................................................................32 
9.1.3
 
Serious Adverse Events ......................................................................................33 
9.2
 
Procedures for Reporting Adverse Events.......................................................34 
9.3
 Reporting a Suspected Unexpected Adverse Reaction ..................................34 
9.3.1
 Reporting a Serious Adverse Event ................................................................34 
9.3.2
 
Procedures for Unmasking (if applicable) .......................................................34 
9.4
 
Type and Duration of the Follow-up of Subjects after Adverse Events ........35 
9.5
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES...................36 
 Study Populations ...............................................................................................36 
10.1
 Intent-to-Treat Population ..............................................................................36 
10.1.1
 Per-Protocol Population .................................................................................36 
10.1.2
 Safety Population ...........................................................................................36 
10.1.3
 General Imputation Methods ............................................................................36 
10.2
 Primary Efficacy Variables ...............................................................................36 
10.3
 Key Secondary Efficacy Variables....................................................................36 
10.4
 Secondary Efficacy VariableS ...........................................................................36 
10.5
 Statistical Hypotheses ........................................................................................37 
10.6
 Sample Size .........................................................................................................37 
10.7
 Demographic and Baseline Medical History ...................................................38 
10.8
 Primary Efficacy Analyses ................................................................................38 
10.9
 Secondary Efficacy Analysis .............................................................................38 
10.10
 Adjustment for Multiplicity ..............................................................................38 
10.11
 Safety Analysis ....................................................................................................39 
10.12
 Statistical Analyses Plan ....................................................................................39 
10.13
 Interim Analysis .................................................................................................39 
10.14
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ...................................39 
 Protection of Human Subjects ..........................................................................39 
11.1
 Subject Informed Consent ..............................................................................39 
11.1.1
 Institutional Review Board (IRB) Approval ..................................................40 
11.1.2
 Ethical Conduct of the Study ............................................................................40 
11.2
 Subject Confidentiality ......................................................................................40 
11.3
 Documentation ....................................................................................................40 
11.4
 Retention of Documentation ..........................................................................40 
11.4.1


Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
11.5
Investigational Product ......................................................................................41 
 Labeling/Packaging ........................................................................................41 
11.5.1
 Storage of Investigational Product .................................................................41 
11.5.2
 Accountability of Investigational Product ......................................................42 
11.5.3
 Final accountability and Disposal of Investigational Product ........................42 
11.5.4
 Recording of Data on Source Documents and Case Reports Forms (CRFs) 42 
11.6
 Handling of Biological Specimens .....................................................................42 
11.7
 Publications .........................................................................................................42 
11.8
12 REFERENCES ...........................................................................................................43 
Appendix 1:  Schedule of Visits and Measurements .....................................................44 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............45 
Appendix 3:  Investigational Product Composition/ Design ........................................52 
Appendix 4:  Handling of Biological Specimens ...........................................................54 
Appendix 5:  Protocol Amendment Summary ..............................................................55 
Appendix 6:  Ora Approvals ...........................................................................................56 
Appendix 7:  Sponsor (Aldeyra) Approvals ..................................................................57 
Appendix 8:  Investigator’s Signature ...........................................................................58 


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Clinical Trial Protocol ADX-102-AC-008 
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LIST OF ABBREVIATIONS 
AC 
allergic conjunctivitis  
AE 
adverse event 
AUC 
area under the curve 
CAC 
Conjunctival Allergen Challenge 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CRO 
contract research organization 
DHHS 
Department of Health and Human Services 
EKG 
electrocardiogram 
ERC 
ethical review committee 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigators’ brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgE 
immunoglobulin-E 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional/independent review board 
ITT 
intent to treat 
LASIK 
laser in situ keratomileusis 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury  
NCS 
not clinically significant 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
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NDA 
new drug application 
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
Ora-CAC® 
Ora- Conjunctival Allergen Challenge 
OS 
left eye 
OU 
both eyes 
OTC 
over the counter 
PHI 
protected health information 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TEAE 
treatment emergent adverse event 
VA 
visual acuity 
 
 


































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Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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Evaluations that may be conducted at an Unscheduled Visit (as appropriate, depending on 
the reason for the visit), include: 
• Update of Medical/Medication History 
• Urine Pregnancy Test 
• Visual Acuity at Distance 
 
• Slit-lamp Biomicroscopy 
• Intraocular Pressure  
• Dilated Fundoscopy  
• Assessment of Adverse Events 
• Assessment of Conjunctival Redness 
 
 
COMPLIANCE WITH PROTOCOL 
8.5
Site staff will review concomitant medication and record any dosing regimen changes 
from previous visits. Concomitant medication information will be recorded in the source 
document and on the eCRF, 
  
Subjects who are inappropriately enrolled or no longer fulfill the trial eligibility criteria 
will be discontinued from the trial. The reason for discontinuation will be recorded as 
 in the source document and in the eCRF.  
All protocol violations, 
 will be recorded in the subject’s source 
document as well as the eCRF. Major protocol violations will be recorded in the subject’s 
source document, entered in the eCRF for randomized subjects, and reported to the IRB, 
as per the applicable regulations.   
 
SUBJECT DISPOSITION 
8.6
 Completed Subjects 
8.6.1
A completed subject is one who has not been discontinued from the trial. 
 Discontinued Subjects 
8.6.2
Subjects may be discontinued prior to the completion of the trial for reasons including, 
but not limited to, the following: 
• 
subject request/withdrawal, 
• 
AEs, 
• 
protocol violations, 
• 
administrative reasons 
 
• 
Sponsor termination of trial, or 
• 
any sound medical reason, as determined by the investigator. 




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Clinical Trial Protocol ADX-102-AC-008 
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CRF. Any clinically relevant deterioration in clinical finding is considered an AE, and 
must be recorded. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event.  
Ocular complaints should not be addressed as AEs unless the complaint is outside the 
normal limits for allergic conjunctivitis symptoms after allergen exposure or is associated 
with clinical sequelae (i.e., adverse slit lamp examination finding). 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning.  
 Severity 
9.1.1
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: 
• 
 
 
 
 
 
 
 
 Relationship to Investigational Product 
9.1.2
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 characterizations will be used:  
• Definitely Related 
• Probably Related 
• Possibly Related 
• Unlikely to be related 
• Not Related 
 
 Expectedness 
9.1.3
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 


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Clinical Trial Protocol ADX-102-AC-008 
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• 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. 
AEs 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 and the Sponsor’s Medical Monitor’s 
determination. 
 
SERIOUS ADVERSE EVENTS 
9.2
An AE is considered serious if, in the view of either the investigator or Sponsor/designee, 
the AE 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/designee, the subject at immediate risk of death as a result 
of the AE.  "Life threatening" 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; or admission to 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; and 


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Clinical Trial Protocol ADX-102-AC-008 
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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, the event 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 
9.3
All AEs and their outcomes must be reported to Ora, the trial Sponsor/designee, and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and governing 
health authorities and recorded on the appropriate eCRF. 
 Reporting a Suspected Unexpected Adverse Reaction 
9.3.1
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the trial 
Sponsor/designee and the IRB/IEC as required by the IRB/IEC, federal, state, or local 
regulations and governing health authorities. 
 Reporting a Serious Adverse Event 
9.3.2
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate CRF.  The investigator is obligated to pursue and obtain information 
requested by Ora and/or the Sponsor/designee in addition to that information reported on 
the CRF.  All subjects experiencing a SAE must be followed up and the outcome 
reported. 
In the event of a SAE, the investigator must notify the appropriate contact in the Study 
Manual immediately; obtain and maintain all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject; provide Ora and the Sponsor/designee a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB of the SAE in a manner according to the IRB guidelines for 
reporting SAEs.  
Collection of AEs/SAEs will begin at the time of informed consent and may be recorded 
up until 30 days post-instillation of IP. 
 
PROCEDURES FOR UNMASKING (IF APPLICABLE) 
9.4
When medically necessary, the investigator may need to determine what treatment has 
been assigned to a subject.  The investigator should make every effort to contact Ora to 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
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discuss the subject’s emergency situation and the need to unmask a trial subject prior to 
unmasking IP.   
If the investigator determines that emergency unmasking is necessary, the investigator 
should identify the given subject’s trial drug 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 in the eCRF that the mask was broken and provide the 
date, time, and reason for breaking the mask.  Any AE or SAE associated with breaking 
the mask must be recorded and reported as specified in this protocol.  The investigator 
has the responsibility to contact Ora within 24 hours of breaking the blind.   
If treatment assignment is unmasked, the IP treatment will be discontinued immediately, 
and the subject will be discontinued from the trial.  
 
TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS 
9.5
AFTER ADVERSE EVENTS 
AEs will be followed until:  
• resolution (return to baseline status or to ‘normal’), 
• stabilization of the event has occurred (no improvement or worsening expected by the 
Investigator), or 
o Note: The principal investigator determines whether the condition is to be 
chronic. Alternatively, the event may be determined to be resolved or resolved 
with sequelae.  
• the event is otherwise explained, regardless of whether the subject is still participating 
in the trial. 
The investigator will follow unresolved adverse events to resolution until the subject is 
lost to follow-up or until the adverse event is otherwise explained. If the subject is lost to 
follow-up, the investigator should make three reasonable attempts to contact the subject 
via telephone or certified mail. All follow-up will be documented in the subject’s source 
document. Non-serious adverse events identified on the last scheduled contact must be 
recorded on the AE eCRF. The status of the AE must be noted and followed as 
aforementioned.  
If the investigator becomes aware of any new information regarding a SAE (e.g., 
resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora Inc. within 24 hours. 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. 












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Clinical Trial Protocol ADX-102-AC-008 
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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 trial records, custody must be transferred to a person who will 
accept the aforementioned responsibility.  The Sponsor must be notified in writing of the 
name and address of the new custodian. 
 LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, AND 
11.5
RETURN OR DISPOSAL OF INVESTIGATIONAL PRODUCT 
 Labeling/Packaging 
11.5.1
The subject kit will be labeled with the following:  
• trial protocol number, 
• contents, 
• randomization number, 
• subject number and initials (manually recorded), 
• storage conditions,  
• Investigational New Drug statement, and 
• Sponsor’s name, address and phone number. 
The foil pouch label will be labeled with the following:  
• trial protocol number, 
• contents, 
• randomization number, 
• storage conditions, 
• Investigational New Drug statement, 
• manufacturer name and address, and 
• Sponsor name, address, and phone number 
 
 Storage of Investigational Product 
11.5.2
 
  
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. The IP will be administered only to subjects entered into the clinical trial, in 
accordance with the conditions specified herein. 


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Clinical Trial Protocol ADX-102-AC-008 
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 Accountability of Investigational Product 
11.5.3
The IP is to only be prescribed by the principal investigator or his/her named sub- 
investigator(s), and is only to be used in accordance with this protocol.  To receive IP, the 
IP must be distributed only to subjects properly qualified under the conditions specified 
herein. 
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 trial.  A detailed inventory must be completed for the IP and available for Sponsor’s 
review during the course of the trial. 
 Final accountability and Disposal of Investigational Product 
11.5.4
At the conclusion of the trial, IP reconciliation will be performed and all remaining IP 
will be destructed and disposed of according to clinical site’s SOP. Sponsor will be 
provided with a final accounting of IP for approval prior to destruction.  
 RECORDING OF DATA ON SOURCE DOCUMENTS AND CASE 
11.6
REPORTS FORMS (CRFS) 
The investigator is responsible for ensuring trial data are completely and accurately 
recorded on each subject’s eCRF, source document, and all trial-related material.  All 
trial 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. 
The Electronic Data Capture for this study will be iMedNet, with access settings 
configured that conform with 21 CFR Part 11 requirements. Only staff that has been 
trained will have access to the system. Subject data will be provided to the sites by 
CD/DVD at the end of the trial. 
 HANDLING OF BIOLOGICAL SPECIMENS 
11.7
Not Applicable. 
 PUBLICATIONS 
11.8
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the trial.  Authorship will be established before writing the manuscript.  Ora 
and the Sponsor will have the final decision regarding the manuscript and publication. 
 
 


Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
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12 REFERENCES 
Ackerman, S., Smith, L.M., and Gomes, P.J. (2016). Ocular itch associated with allergic 
conjunctivitis: latest evidence and clinical management. Ther. Adv, Chronic Dis. 7(1), 52-
67. 
Albrecht S. Conjunctivitis. US Pharm. 2011;36(4):29-34.  
Bacsi A, Dharajiya N, Choudhury BK, Sur S, Boldogh I. Effect of pollen-mediated oxidative 
stress on immediate hypersensitivity reactions and late-phase inflammation in allergic 
conjunctivitis. J Allergy Clin Immunol. 2005;116(4):836-843.  
Leonardi, A. (2013). Allergy and allergic mediators in tears. Exp. Eye Res. 117, 106-117. 
 
Mishra G, Tamboli V, Jwala J, Mitra A. Recent patents and emerging therapeutics in the 
treatment of allergic conjunctivitis. Inflamm Allergy Drug Discov. 2011;5(1):26-36. 
Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United 
States, 1988-1994. J Allergy Clin Immunol. 2010;126(4):778-783.  
 
 


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APPENDIX 1:  SCHEDULE OF VISITS AND MEASUREMENTS 
 
 
 


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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, 
EQUIPMENT, AND TECHNIQUES 


Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
Confidential 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
Confidential 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
Confidential 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
Confidential 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
Confidential 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
Confidential 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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APPENDIX 4:  HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 


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Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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APPENDIX 5:  PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 






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Clinical Trial Protocol ADX-102-AC-008 
Final 1.0, 15 February 2018 
 
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APPENDIX 8:  INVESTIGATOR’S SIGNATURE 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, Parallel-Group, 
Vehicle-Controlled, Phase 3, Clinical Trial to Assess the Safety 
and Efficacy of Reproxalap Ophthalmic Solutions (0.25% and 
0.5%) Compared to Vehicle in the Conjunctival Allergen 
Challenge (Ora-CAC®) Model of Acute Allergic Conjunctivitis  
Protocol Number: 
ADX-102-AC-008 
Final Date: 
15 February 2018 
I agree to implement and conduct the trial 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, 
Double-Masked, 
Randomized, 
Parallel-Group, 
Vehicle-Controlled, Phase 3 Clinical Trial to Assess the Safety and 
Efficacy of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
Compared to Vehicle in the Conjunctival Allergen Challenge (Ora-
CAC®) Model of Acute Allergic Conjunctivitis 
 
 
 
 
 
 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
131 Hartwell Ave. 
 
 
 
Lexington, MA 02421 
 
 
 
 
Protocol Number: 
ADX-102-AC-008 
 
 
Author:   
 
 
 
 
 
Date:    
 
20FEB2019 
Version:  
 
1.0 
 
 
 
 
 




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Table of Contents 
1. 
Introduction .............................................................................................................................. 6 
2. 
Study Objectives ...................................................................................................................... 6 
3. 
Study Design and Procedures ................................................................................................. 6 
3.1 General Study Design .............................................................................................................. 6 
3.2 Schedule of Visits and Assessments ....................................................................................... 7 
4. 
Study Endpoints ....................................................................................................................... 8 
4.1 Primary Efficacy Endpoints ...................................................................................................... 8 
4.2 Key Secondary Efficacy Endpoint ............................................................................................ 8 
4.3 Additional Secondary Efficacy Variables ................................................................................. 8 
4.4 Safety Variables ....................................................................................................................... 8 
4.5 Statistical Hypotheses .............................................................................................................. 9 
5. 
Study Treatments ..................................................................................................................... 9 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 10 
5.2 Masking and Unmasking ........................................................................................................ 10 
6. 
Sample Size and Power Considerations ............................................................................... 10 
7. 
Data Preparation .................................................................................................................... 11 
8. 
Analysis Populations .............................................................................................................. 12 
8.1 Intent-to-Treat ........................................................................................................................ 12 
8.2 Per-Protocol ........................................................................................................................... 12 
8.3 Safety ..................................................................................................................................... 12 
9. 
General Statistical Considerations ......................................................................................... 12 
9.1 Unit of Analysis ...................................................................................................................... 12 
9.2 Missing or Inconclusive Data Handling .................................................................................. 12 
9.3 Definition of Baseline ............................................................................................................. 14 
9.4 Data Analysis Conventions .................................................................................................... 14 
9.5 Adjustments for Multiplicity .................................................................................................... 15 
10. 
Disposition of Subjects ........................................................................................................... 15 
11. 
Demographic and Pretreatment Variables ............................................................................. 16 
11.1 Demographic Variables .......................................................................................................... 16 
11.2 Pretreatment Variables .......................................................................................................... 16 
12. 
Medical History and Concomitant Medications ...................................................................... 17 
12.1 Medical History ...................................................................................................................... 17 
12.2 Concomitant Medications ....................................................................................................... 17 
13. 
Exposure to Investigational Product ...................................................................................... 17 


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14. 
Efficacy Analyses ................................................................................................................... 18 
14.1 Primary Analysis .................................................................................................................... 18 
14.2 Secondary Analyses .............................................................................................................. 19 
14.2.1 
Ocular Itching Responders Analysis .......................................................................... 19 
14.2.2 
Time to Response ...................................................................................................... 21 
14.2.3 
Ocular Itching ............................................................................................................. 22 
15. 
Safety Analyses ..................................................................................................................... 23 
15.1 Adverse Events/Adverse Drug Reactions .............................................................................. 24 
15.2 Visual Acuity........................................................................................................................... 25 
15.3 Slit-Lamp Biomicroscopy Examination .................................................................................. 25 
15.4 Intraocular Pressure ............................................................................................................... 26 
15.5 Dilated Fundoscopy Examination .......................................................................................... 26 
15.6 Conjunctival Redness ............................................................................................................ 26 
16. 
Interim Analyses .................................................................................................................... 27 
17. 
Changes from Protocol-Stated Analyses ............................................................................... 27 
18. 
Revision History ..................................................................................................................... 27 
19. 
Tables .................................................................................................................................... 27 
20. 
Listings ................................................................................................................................... 29 
21. 
Figures ................................................................................................................................... 30 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
AUCt1-t2 
Area Under the Curve 
 
CAC 
Conjunctival Allergen Challenge 
CI 
Confidence Interval 
CS 
Clinically Significant (when used in the context of safety); Compound 
Symmetric (when used in the context of covariance structures) 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
GEE 
Generalized Estimating Equation 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
LM 
Linear Model 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Squares 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 
NCS 
Not Clinically Significant 
OD 
Right Eye 
OS 
Left Eye 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
VA 
Visual Acuity 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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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-AC-008, Version 1.0 dated 15FEB2018. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required to supplement 
the planned analyses described in this SAP, they may be completed as post-hoc analyses and will be 
identified as such in the clinical study report. 
2. Study Objectives 
The objective of this study is to evaluate the safety and efficacy of Reproxalap Ophthalmic Solutions 
(0.25% and 0.5%) compared to Vehicle Ophthalmic Solution for the treatment of ocular itching 
associated with acute allergic conjunctivitis. 
3. Study Design and Procedures 
3.1 General Study Design 
This is a multi-center, double-masked, randomized, parallel-group, vehicle-controlled Phase 3 clinical 
trial will enroll approximately 
 to evaluate the safety and efficacy of Reproxalap Ophthalmic 
Solutions (0.25% and 0.5%) compared to Vehicle Ophthalmic Solution for the treatment of ocular itching 
associated with acute (seasonal) allergic conjunctivitis.  
The trial will be comprised of 
 
 
 
Subjects who meet the entry 
criteria for itching and redness response 
 
 to receive bilateral administration of either Reproxalap Ophthalmic 
Solution 0.25%, Reproxalap Ophthalmic Solution 0.5%, or Vehicle Ophthalmic Solution. 
 
 
 
 






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• 
Adverse Events (AE) (reported, elicited, and observed); 
• 
Visual Acuity (VA) 
 
 
• 
Slit-lamp Biomicroscopy; 
• 
Intraocular Pressure (IOP); 
• 
Dilated Fundoscopy; 
• 
Conjunctival Redness. 
4.5 Statistical Hypotheses 
The null and alternative hypotheses, based on the primary and key secondary efficacy endpoints, are 
as follows: 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
To control the overall Type I error rate, 
 
 
5. Study Treatments 
The study consists of three treatment arms: 
 
• 
Reproxalap Ophthalmic Solution 0.25%; 
• 
Reproxalap Ophthalmic Solution 0.5%; 


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• 
Vehicle Ophthalmic Solution. 
5.1 Method of Assigning Subjects to Treatment Groups 
All subjects screened for the trial who sign an informed consent form will be assigned a 3-digit screening 
number that will be entered in the Screening and Enrollment Log. Screening numbers will be assigned 
in a sequential order beginning with 001. Randomization will be used to avoid bias in the assignment of 
subjects to treatments, to increase the likelihood that known and unknown subject attributes 
 
 
 
 
Once a subject meets all qualification criteria 
 they will be enrolled and randomly 
assigned to masked treatment 
 
. Subjects will be assigned 
the lowest 4-digit randomization number available at the investigative site within the appropriate stratum. 
 
 
  
5.2 Masking and Unmasking 
When medically necessary, the investigator may need to determine what treatment has been assigned 
to a subject. The investigator should make every effort to contact Ora to discuss the subject’s emergency 
situation and the need to unmask a trial subject prior to unmasking IP. 
If the investigator determines that emergency unmasking is necessary, the investigator should identify 
the given subject’s trial drug 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 in the electronic case report form (eCRF) that the mask 
was broken and provide the date, time, and reason for breaking the mask. Any AE or serious AE (SAE) 
associated with breaking the mask must be recorded and reported as specified in this protocol. The 
investigator has the responsibility to contact Ora within 24 hours of breaking the blind. 
If treatment assignment is unmasked, the IP will be discontinued immediately, and the subject will be 
discontinued from the trial. 
6. Sample Size and Power Considerations 
 
 


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7. Data Preparation 
All reported study data will be recorded on the eCRFs supplied by SDC 
.  Only the 
Principal Investigator and authorized study staff according to the Delegation of Responsibilities log are 
entitled to make entries in the eCRF.   
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 the Sponsor and Ora in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
 
 
 
 
 
  
 
 
 
 


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8. Analysis Populations 
8.1 Intent-to-Treat 
The Intent-to-Treat (ITT) population consists of 
 
 
 
8.2 Per-Protocol 
The Per-Protocol (PP) population is 
 
 
. 
8.3 Safety 
The Safety population includes 
 
 
 
9. General Statistical Considerations 
9.1 Unit of Analysis 
 
 
 
 
 
 
 
9.2 Missing or Inconclusive Data Handling 
The primary analysis of ocular itching will be conducted 
 
  
 
 
 
 
 
 
 
 
  
 


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. 
Subject listings will be provided 
 
. 
Protocol violations will be summarized 
 
 
 
 
 
 A subject listing will be provided 
 
 
 
11. Demographic and Pretreatment Variables 
11.1 
Demographic Variables 
The demographic variables collected 
  
 
 
 
 
 
 
 
 
 
 
A subject listing that includes all demographic variables will be provided. 
11.2 
Pretreatment Variables 
 
 
will be provided in a subject listing. 






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14.2 
Secondary Analyses 
14.2.1 Ocular Itching Responders Analysis 
The key secondary efficacy endpoint 
 
 
 
 
 
 


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15.1 
Adverse Events/Adverse Drug Reactions 
AEs, SAEs and adverse drug reactions are defined in the study protocol. All AEs will be coded using 
MedDRA 21.0. Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or 
worsens on or after the day that randomized study treatment is initiated.   
Relationship to IP 
The relationship of each AE to the IP should be determined by the investigator using the following 
categories: 
• 
Not related; 
• 
Unlikely to be related; 
• 
Possibly related; 
• 
Probably related;  
• 
Definitely related. 
 
 
 
Severity 
Severity will be classified as mild, moderate or severe. Missing severity for AEs and TEAEs will be 
counted as ‘Severe’.  
• 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
Subject listings will be provided for all AEs, SAEs, AEs leading to death, and AEs leading to study 
treatment discontinuation. 
15.2 
Visual Acuity  
VA will be measured 
 
 
 
 
 
Results for VA will be presented in a data listing.  
15.3 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination will be performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A subject listing of the slit-lamp biomicroscopy parameters will also be produced. 
15.4 
Intraocular Pressure  
IOP will be measured 
 
 
 
 
 IOP will be listed for each eye at each visit. 
15.5 
Dilated Fundoscopy Examination 
Dilated fundus examinations will be performed 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 Results will be listed for both eyes at each visit. 
15.6 
Conjunctival Redness 
Conjunctival redness will be assessed