Conditions: Allergic Conjunctivitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
A Multi-Center, Double-Masked, Randomized, Parallel-Group, Vehicle-Controlled, Methodology Development Environmental Clinical Trial with Reproxalap Ophthalmic Solutions (0.25% and 0.5%) in Subjects with Seasonal 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 four times a day and an additional four times a day on an as needed basis. intervention 2: Reproxalap Ophthalmic Solution (0.5%) administered four times a day and an additional four times a day on an as needed basis. intervention 3: Vehicle Ophthalmic Solution administered four times a day and an additional four times a day on an as needed basis.

Protocol document:
Prot_000.pdf: 
Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
  
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
Confidential 
 
 
Page 1 of 69 
 
Clinical Trial Protocol: ADX-102-AC-010 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Parallel-Group, Vehicle-Controlled, 
Environmental Clinical Trial with Reproxalap 
Ophthalmic Solutions (0.25% and 0.5%) in 
Subjects with Seasonal Allergic Conjunctivitis 
Protocol Number: 
ADX-102-AC-010 
Study Phase: 
1b 
 
Investigational Product 
Name: 
Reproxalap Ophthalmic Solutions (0.25% and 
0.5%) 
 
IND/IDE/PMA Number: 
 
 
Indication: 
Seasonal allergic conjunctivitis 
 
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 
 
IRB/IEC: 
 
 
 
 
 
Date 
Original Protocol: 
15 June 2018 
Version 2.0: 
24 August 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. 
 


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SPONSOR (Aldeyra) PERSONNEL 
Chief Medical Officer: 
 
  
 
ORA PERSONNEL 
Chief Medical Officer: 
 
 
 
Department Vice President, 
Allergy: 
 
 
 
Project Lead: 
 
 
 
 
MEDICAL MONITOR 
Medical Monitor: 
  
 
 
 




















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Clinical Trial Protocol: ADX-102-AC-010  
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TABLE OF CONTENTS 
Clinical Trial Protocol: ADX-102-AC-010 .........................................................................1 
SYNOPSIS ...........................................................................................................................3 
TABLE OF CONTENTS ...................................................................................................12 
LIST OF ABBREVIATIONS ............................................................................................15 
1 
INTRODUCTION ....................................................................................................17 
2 
CLINICAL STUDIES OF REPROXALAP OPHTHALMIC SOLUTION .............19 
2.1 
Minimization of Risk ......................................................................................21 
3 
EXPLORATORY OBJECTIVES .............................................................................22 
4 
CLINICAL HYPOTHESES .....................................................................................22 
5 
OVERALL STUDY DESIGN ..................................................................................22 
6 
STUDY POPULATION ...........................................................................................23 
 
Number of Subjects (approximate) ................................................................23 
 
Study Population Characteristics ....................................................................23 
 
Inclusion Criteria ............................................................................................23 
 
Exclusion Criteria ...........................................................................................24 
 
Withdrawal Criteria (if applicable) ................................................................25 
7 
STUDY PARAMETERS ..........................................................................................26 
 
Exploratory Efficacy and Safety Measures ....................................................26 
7.1.1 
Exploratory Efficacy Measuress .......................................................26 
7.1.2 
Safety Measures ................................................................................26 
7.1.3 
Criteria for Effectiveness ..................................................................27 
8 
STUDY MATERIALS .............................................................................................27 
 
Study Treatment(s) .........................................................................................27 
8.1.1 
Study Treatment(s)/ Formulation(s) .................................................27 
8.1.2 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s). .......................27 
8.1.3 
Instructions for Use and Administration ...........................................27 
 
Other Clinical Trial Supplies ..........................................................................28 
9 
STUDY METHODS AND PROCEDURES ............................................................28 
 
Subject Entry Procedures ...............................................................................28 
9.1.1 
Overview ...........................................................................................28 
9.1.2 
Informed Consent..............................................................................29 
9.1.3 
Washout Intervals .............................................................................29 
9.1.4 
Procedures for Final Study Entry ......................................................29 
9.1.5 
Methods for Assignment to Treatment Groups: ...............................29 
 
Concurrent Therapies .....................................................................................29 
9.2.1 
Prohibited Medications/Treatments ..................................................30 
9.2.2 
Escape Medications ..........................................................................30 
9.2.3 
Special Diet or Activities ..................................................................30 
 
Examination Procedures .................................................................................30 
9.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................30 
9.3.2 
Visit 1 
 Screening/ Informed Consent/ Skin 
Test ....................................................................................................30 




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  Protection of Human Subjects ........................................................................47 
12.1.1  Subject Informed Consent.................................................................47 
12.1.2  Institutional Review Board Approval ...............................................48 
  Ethical Conduct of the Study ..........................................................................48 
  Subject Confidentiality ...................................................................................48 
  Documentation ...............................................................................................48 
12.4.1  Retention of Documentation .............................................................48 
  Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ...................................................................................49 
12.5.1  Labeling/Packaging ...........................................................................49 
12.5.2  Storage of Investigational Product ....................................................49 
12.5.3  Accountability of Investigational Product ........................................50 
12.5.4  Return or Disposal of Investigational Product ..................................50 
  Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ..........................................................................................................50 
  Publications ....................................................................................................50 
13 
REFERENCES .........................................................................................................51 
14 
APPENDICES ..........................................................................................................52 
Appendix 1: Schedule of Visits and Measurements ..........................................................52 
Appendix 2: Pollen counts .................................................................................................53 
Appendix 3: Examination Procedures, Tests, & Evaluations ............................................54 
Appendix 4: Sample Dosing and Allergic Sympton Diaries .............................................61 
Appendix 5: Protocol Amendment ....................................................................................66 
Appendix 6: Ora Approvals ...............................................................................................67 
Appendix 7: Sponsor (ALDEYRA) Approvals .................................................................68 
Appendix 8: Investigator’s Signature ................................................................................69 
 
 


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LIST OF ABBREVIATIONS 
AC 
allergic conjunctivitis  
ACQLQ 
Allergic Conjunctivitis Quality of Life Questionnaire 
AE 
adverse event 
API 
active pharmaceutical ingredient 
ANCOVA 
analysis of covariance  
AUC 
area under the curve 
BCVA 
best-corrected visual acuity 
CAC 
Conjunctival Allergen Challenge  
CD 
compact disc 
CFR 
Code of Federal Regulations 
CPT 
Current Procedural Terminology 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
ERC 
Ethical Review Committee 
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 Council for Harmonisation 
IgE 
immunoglobin-E 
IEC 
Independent Ethics Committee 
IM 
intramuscular 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intention-to-treat 
LASIK 
laser in situ keratomileusis 
logMAR 
logarithm of the minimum angle of resolution 
MCMC 
Markov Chain Monte Carlo 


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MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury  
MMRM 
mixed model repeated measures 
NCS 
not clinically significant 
ND  
not done  
NDA 
new drug application 
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
OU 
both eyes 
OTC 
over the counter 
PBS 
phosphate buffered saline 
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  
SAC 
seasonal allergic conjunctivitis  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event  
USP 
United States Pharmacopeia 
VA 
visual acuity 
w/v 
weight per unit volume 
 
 














































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 Monitoring and Quality Assurance 
During the course of the clincal trial an Ora, Inc. monitor, or designee, will make routine 
site visits to review protocol compliance, assess IP accountability, and ensure the clinical 
trial is being conducted according to the pertinent regulatory requirements. The review of 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the clinical trial monitoring will be outlined in a 
monitoring plan. 
Regulatory authorities of domestic and foreign agencies, quality assurance, or designees 
may carry out on-site inspections and audits, which may include source data checks. 
Therefore, direct access to the original source data will be required for inspections and 
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 
An AE is defined as any untoward medical occurrence associated with the use of  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, in response to an open question from 
clinical trial 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 eCRF. 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. Any pre-existing 
medical condition that worsens after administration of study medication will also be 
considered a new adverse event. Study medication includes the drug under evaluation or 
any other medications required by the protocol given during any stage of the clinical trial. 
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). 


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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. 
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 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 characterizations 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 IB or is not listed at the specificity or 
severity that has been observed. 
 Expected:  an AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not applicable: an AE unrelated to the IP. 
AE events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 


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Clinical Trial Protocol: ADX-102-AC-010  
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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 determination of the Sponsor’s Medical Monitor. 
 Serious Adverse Events 
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 
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 


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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 
All AEs and their outcomes must be reported to Ora, Inc., the Sponsor, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate eCRF. Collection of AEs/SAEs will begin at 
the time of informed consent and may be recorded up until 30 days post-instillation of IP. 
10.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, Inc., the Sponsor 
and the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 
10.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate eCRF.  The investigator is obligated to pursue and obtain information 
requested by Ora, Inc. and/or the Sponsor/designee in addition to that information 
reported on the eCRF.  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 Safety 
Management Plan 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, Inc. 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.  
 Procedures for Unmasking (if applicable) 
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, Inc. 
to discuss the subject’s emergency situation and the need to unmask a clinical trial 
subject prior to unmasking IP.   
If the investigator determines that emergency unmasking is necessary, the investigator 
should identify the given subject’s clinical 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 










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Clinical Trial Protocol: ADX-102-AC-010  
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The secondary safety variables of visual acuity, slit-lamp biomicroscopy, IOP, and 
dilated fundoscopy will be summarized 
 
 
 Statistical Analysis Plan 
Prior to database lock, the Sponsor will finalize a statistical analysis plan (SAP) that will 
detail all planned analyses. Any analyses conducted in addition to those specified in the 
SAP will be clearly documented as post hoc. 
 Interim Analysis 
No interim analyses are planned. 
12 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This clinical trial will be conducted in compliance with the protocol, current GCPs, 
including the International Council 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 
12.1.1 Subject Informed Consent 
Informed consent must take place before any clinical trial specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each subject 
or from the subject’s parent or legal guardian prior to enrollment into the clinical trial (if 
applicable). 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 ICFs must be approved for use by the Sponsor and receive approval 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, Inc. prior to submission 
to the governing IRB and that it is read, signed and dated by all subjects, subsequently 
enrolled in the clinical trial, as well as those currently enrolled in the clinical trial. 
If informed consent is taken under special circumstances (e.g., oral informed consent), 
then the procedures to be followed must be agreed to by Ora, Inc. and Sponsor and 
provided in writing by Ora, Inc. and Sponsor prior to the consent process. 


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12.1.2 Institutional Review Board Approval 
The clinical trial 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 
clinical trial and re-approval at least annually. 
Only an IRB approved version of the informed consent form will be used. 
 Ethical Conduct of the Study 
The clinical trial will be conducted in accordance with the ethical principles that 
originated with the Declaration of Helsinki. 
 Subject Confidentiality 
All personal clinical trial subject data collected and processed for the purposes of the 
clinical trial should be maintained by the investigator and site staff with adequate 
precautions as to ensure that the confidentiality of the data is in accordance with local, 
state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, Inc., the Sponsor, the 
IRB/IEC approving this clinical trial, the Food and Drug Administration (FDA), the 
Department of Health and Human Services, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the subject’s original 
medical and clinical trial records for verification of the data and 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 clinical trial 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 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s clinical trial subject files, as well as the results of diagnostic tests such 
as X-rays, laboratory tests, and electrocardiograms. The investigator’s copy of the eCRFs 
serves as the investigator’s record of a subject’s clinical trial-related data. 
12.4.1 Retention of Documentation 
All clinical trial related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of eCRFs 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 




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12.5.3 Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or the 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 clinical trial. A detailed inventory must be completed for the IP. 
12.5.4 Return or Disposal of Investigational Product 
At the conclusion of the clinical 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 Electronic Case 
Reports Forms (eCRFs) 
The investigator is responsible for ensuring clinical trial data is completely and accurately 
recorded on each subject’s eCRF, source document, and all clinical trial-related material. 
All clinical 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. 
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 clinical trial 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. 
 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the clinical trial. Authorship will be established before writing the 
manuscript. Ora, Inc. and the Sponsor will have the final decision regarding the 
manuscript and publication. 
 
 


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13 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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14 
APPENDICES 


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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
  
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
 
Confidential 
 
 
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
 
Confidential 
 
 
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
 
Confidential 
 
 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
  
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
 
Confidential 
 
 
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
 
Confidential 
 
 
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Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
  
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Clinical Trial Protocol: ADX-102-AC-010  
Version 2.0, 24 August 2018 
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APPENDIX 5: PROTOCOL AMENDMENT 
 
 
 






Reproxalap Ophthalmic Solutions (0.25% and 0.5%) 
  
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Clinical Trial Protocol: ADX-102-AC-010  
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APPENDIX 8: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Parallel-Group, Vehicle-Controlled, Environmental 
Clinical Trial with Reproxalap Ophthalmic 
Solutions (0.25% and 0.5%) in Subjects with 
Seasonal Allergic Conjunctivitis 
Protocol Number:                   ADX-102-AC-010 
Final Date:  
24 August 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, Inc. 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, Environmental Clinical Trial with Reproxalap 
Ophthalmic Solutions (0.25% and 0.5%) in Subjects with Seasonal 
Allergic Conjunctivitis 
 
 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
131 Hartwell Ave. 
 
 
 
Lexington, MA 02421 
 
 
 
 
Protocol Number: 
ADX-102-AC-010 
 
 
Author:   
 
 
 
 
 
Date:    
 
23JAN2019 
Version:  
 
2.0 
 
 
 
 
 
 
 
 




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Table of Contents 
1. 
Introduction .............................................................................................................................. 7 
2. 
Study Objectives ...................................................................................................................... 7 
3. 
Study Variables ........................................................................................................................ 7 
3.1 Exploratory Efficacy Variables ................................................................................................. 7 
3.2 Safety Variables ....................................................................................................................... 8 
3.3 Statistical Hypotheses .............................................................................................................. 8 
4. 
Study Design and Procedures ................................................................................................. 8 
4.1 General Study Design .............................................................................................................. 8 
4.2 Schedule of Visits and Assessments ..................................................................................... 10 
5. 
Study Treatments ................................................................................................................... 11 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 11 
5.2 Masking and Unmasking ........................................................................................................ 11 
6. 
Sample Size and Power Considerations ............................................................................... 12 
7. 
Data Preparation .................................................................................................................... 12 
8. 
Analysis Populations .............................................................................................................. 12 
8.1 Intent-to-Treat ........................................................................................................................ 12 
8.2 Per Protocol ........................................................................................................................... 12 
8.3 Safety ..................................................................................................................................... 13 
9. 
General Statistical Considerations ......................................................................................... 13 
9.1 Unit of Analysis ...................................................................................................................... 13 
9.2 Missing or Inconclusive Data Handling .................................................................................. 13 
9.3 Definition of Baseline ............................................................................................................. 14 
9.4 Data Analysis Conventions .................................................................................................... 15 
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 ...................................................................... 16 
12.1 Medical History ...................................................................................................................... 16 
12.2 Concomitant Medications ....................................................................................................... 17 
13. 
Dosing Compliance and Treatment Exposure ....................................................................... 17 
13.1 Treatment Exposure .............................................................................................................. 17 
13.2 Dosing Compliance ................................................................................................................ 18 




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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ACQLQ 
Allergic Conjunctivitis Quality of Life Questionnaire 
AR1 
Autoregressive 1 (covariance structure)  
ATC 
Anatomical Therapeutic Chemical Classification 
AUC 
Area Under the Curve 
AUCt1-t2 
Area Under the Curve 
 
CAC 
Conjunctival Allergen Challenge 
CRF 
Case Report Form 
CI 
Confidence Interval 
CS 
Clinically Significant 
CS 
Compound Symmetric (covariance structure) 
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 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Squares 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model with Repeated Measures 
NCS 
Not clinically significant 
PDF 
Portable Document Format 
PP 
Per Protocol 
PRN 
As Needed 
PT 
Preferred Term 
QID 
Four Times Daily 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TOEP 
Toeplitz (covariance structure) 
VA 
Visual Acuity 


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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-010, Version 2.0 dated 24AUG2018. 
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 in the clinical study report as such. 
2. Study Objectives 
The exploratory objectives of this study are the following: 
• 
Evaluate the feasibility of a novel, 
 dosing regimen 
of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) in an environmental clinical trial design. 
• 
Evaluate the efficacy of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) on the signs and 
symptoms associated with seasonal allergic conjunctivitis during allergy season in an 
environmental clinical trial design that utilizes a daily diary. 
• 
Evaluate the safety of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) in an environmental 
clinical trial design. 
3. Study Variables 
3.1 
Exploratory Efficacy Variables 
The exploratory efficacy endpoints are the following: 
• 
ocular itching scores 
 
 
• 
ocular redness scores 
 
 
• 
 
 
 


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• 
 assessments for eyelid swelling and tearing/watery eyes 
 
 
• 
Assessments 
:  
o 
Ocular redness 
;  
o 
Ocular itching 
;  
o 
Ocular redness 
  
o 
Eyelid swelling 
  
o 
Tearing/watery eyes 
. 
• 
Allergic Conjunctivitis Quality of Life Questionnaire (ACQLQ) 
 
3.2 
Safety Variables 
The safety variables include the following: 
• 
Adverse Events (AE) (reported, elicited, and observed); 
• 
Visual Acuity (VA) 
 
 
• 
Slit-lamp Biomicroscopy; 
• 
Intraocular Pressure (IOP); 
• 
Dilated Fundoscopy. 
3.3 
Statistical Hypotheses 
This early phase (1b), exploratory clinical trial is designed to assess the safety, tolerability, and 
pharmacodynamic activity of Reproxalap Ophthalmic Solution. Consequently, there are no primary 
endpoints and no formal statistical hypotheses. 
4. Study Design and Procedures 
4.1 
General Study Design 
This is a multi-center, double-masked, randomized, parallel-group, vehicle-controlled, Phase 1b 
methods environmental clinical trial to evaluate Reproxalap Ophthalmic Solution (0.25%) and 
Reproxolap Ophthalmic Solution (0.5%) compared to Vehicle Ophthalmic Solution in subjects with 
seasonal allergic conjunctivitis. 
 
 
 
Subjects will sign the informed consent form at Visit 1 
 and will undergo an allergic 
skin test,
. At Visit 2 
 each qualifying subject will undergo a bilateral conjunctival 
allergen challenge (CAC) titration 
. Subjects who test positively will be dispensed 




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4.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided below. 


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5. Study Treatments 
The study consists of three treatment arms: 
• 
Reproxalap Ophthalmic Solution (0.25%); 
• 
Reproxalap Ophthalmic Solution (0.5%); 
• 
Vehicle Ophthalmic Solution. 
5.1 
Method of Assigning Subjects to Treatment Groups 
All subjects screened for the clinical trial who sign an informed consent form will be assigned a three-
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. 
Each subject who meets all the inclusion and none of the exclusion criteria at Visit 3 
 will be 
assigned the lowest 4-digit randomization number available at the given investigative site. Subjects will 
be randomly assigned to masked treatment 
 
 
 
 
 
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 the medical monitor at Ora, Inc. to 
discuss the subject’s emergency situation and the need to unmask a clinical trial subject prior to 
unmasking the IP. 
If the investigator determines that emergency unmasking is necessary, the investigator should identify 
the given subject’s clinical 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 serious AE (SAE) associated with 
breaking the mask must be recorded and reported as specified in the protocol. The investigator has the 
responsibility to contact Ora, Inc. 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 clinical trial. 








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9.4 
Data Analysis Conventions 
All data analysis will be performed by SDC.  Statistical programming and analyses will be performed 
using SAS® 
  
 
 
 
 
 
 
 
 
 
  
 
     
  
  
 
 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, 
visit. 
9.5 
Adjustments for Multiplicity 
 
 
10. Disposition of Subjects 
Subject disposition will be presented 
 
 
 
 
 
 
 
 
. 


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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 
At Screening, subjects signing the informed consent and Health Insurance Portability and Accountability 
Act (HIPAA) forms may be given a diagnostic test for allergic disease 
 Results 
 
will be provided in a subject listing. 
12. Medical History and Concomitant Medications 
12.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
 


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.   
Listings of medical history will be generated 
. 
12.2 
Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug Dictionary 
 
 
 
 
 
 
 
 
  
 
 
 
  Listings of concomitant medications will be generated 
 
13. Dosing Compliance and Treatment Exposure 
At Visit 3 
subjects will receive their first dose of IP in clinic and will be dispensed additional IP 
for at-home dosing. 
 
 
 
 
 
13.1 
Treatment Exposure 
Treatment exposure will be obtained 
 
 
 
 


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IP instillation data for all subjects will also be provided in listings. 
13.2 
Dosing Compliance 
Treatment compliance will be assessed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Data pertaining to study drug assignment, instillation, accountability, etc., will be presented in subject 
listings. 
14. Exploratory Efficacy Analyses 
14.1 
Subject Diary Data 
Beginning after Visit 3 
 and continuing to Visit 5 (
 subjects are instructed to record allergic 
signs and symptoms 
 
 
 
 
 
 
 
 
14.1.1 Ocular Itching Subject Diary Scores 
Ocular itching will be evaluated 
 
 
    
 
 
 
 
 
 
 
 
 
 
 






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Figures will be created 
 
 
 
14.1.2 Ocular Itching Subject Diary Scores - Responders 
The ocular itching diary data will also be analyzed 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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14.1.4 Eyelid Swelling and Tearing/Watery Eyes Subject Diary Scores 
Eyelid swelling will be evaluated
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
14.2 
Scheduled Visit Ophthalmic Evaluations 
The following assessments will be conducted 
 
 
• 
Ocular redness 
  
• 
Ocular itching 
  
• 
Ocular redness 
;  
• 
Eyelid swelling
;  
• 
Tearing/watery eyes 
 
Each of these assessments will be analyzed 
 
 
 
 
: 




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A subject listing of ACQLQ results will also be provided. 
15. Safety Analyses 
All safety analyses will be conducted 
 
 
 
 
15.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an IP in humans, 
whether or not considered IP-related.  An AE can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, without 
any judgment about causality. An AE can arise from any use of the IP (e.g., off-label use, use in 
combination with another drug or medical device) and from any route of administration, formulation, or 
dose, including an overdose. Additional details surrounding the definition of an AE, including SAEs, can 
be found in the study protocol. All AEs will be coded using MedDRA 21.0. 
Treatment-emergent adverse events (TEAE) are defined as any event that occurs or worsens on or after 
the day that randomized study treatment is initiated.   
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;  


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• 
Definitely related. 
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: 
• 
 
 
 
 
 
 
 
 
An overall summary will be presented that includes the number of AEs and the number and percentage 
of subjects who experienced at least one AE, by treatment group and for all subjects combined.  This 
summary will also include breakdowns of AEs further categorized as ocular or non-ocular, SAEs, AEs 
by maximum severity and relationship to IP, number of subjects with AEs leading to treatment withdrawal 
and number of subjects with AEs resulting in death. TEAEs summarized for the same categories will 
also be included. 
Additional summaries of AEs will be provided showing the number and percentage of subjects who 
experienced at least one AE.  These summaries will be presented at the subject level by SOC and PT.  
If a subject reports the same PT multiple times within the same SOC, that PT will only be reported once 
within that SOC.  As with the PT, if a subject reports multiple conditions within the same SOC, that SOC 
will only be reported once.  In the summary, SOC will be listed in ascending alphabetical order; PTs will 
be listed in order of descending frequency for all subjects within each SOC.  These summaries will be 
presented for ocular and non-ocular AEs separately and include the following: 
• 
All AEs; 
• 
All TEAEs; 
• 
All TEAEs related to the IP (includes AEs possibly, probably or definitely related to IP); 
• 
All SAEs; and 
• 
All TEAEs by maximal severity. 
Subject listings will be provided for all AEs, SAEs, AEs leading to death and AEs leading to study 
treatment discontinuation. 


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15.2 
Visual Acuity  
VA will be measured 
 
 
 
 
 Results for VA will be presented in a subject listing.  
15.3 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination will be performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A subject listing of the slit-lamp biomicroscopy parameters will also be produced. 
15.4 
Intraocular Pressure 
IOP will be measured 
 
 
 
 
 
15.5 
Dilated Fundoscopy Examination 
Dilated fundus examinations will be performed 
 
 
 
  
 
 


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16. Interim Analyses 
No interim analysis is planned for this study. 
17. Changes from Protocol-Stated Analyses 
. 
18. References 
[1] Abelson, M. B., Chambers, W. A., & Smith, L. M. (1990). Conjunctival allergen challenge: a clinical 
approach to studying allergic conjunctivitis. Archives of ophthalmology, 108(1), 84-88. 
19. Revision History