Conditions: Conjunctivitis, Allergic
Keywords: ADX-102 Allergic Conjunctivitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 154
Healthy volunteers: no

Brief summary:
A Multi-Center, Double-Masked, Randomized, Vehicle-Controlled, Phase 2b Evaluation of the Onset and Duration of ADX-102 Ophthalmic Drops (0.5% and 0.1%) Compared to Vehicle of ADX-102 Ophthalmic Drops in the Conjunctival Allergen Challenge (Ora-CAC®) Model of Acute Allergic Conjunctivitis.

Detailed description:

Arms:
arm 1: ADX-102 Ophthalmic Drops (0.5%) administered twice in two weeks. arm 2: ADX-102 Ophthalmic Drops (0.1%) administered twice in two weeks. arm 3: Vehicle of ADX-102 Ophthalmic Drops

Interventions: intervention 1: ADX-102 Ophthalmic Drops (0.5%) intervention 2: ADX-102 Ophthalmic Drops (0.1%) intervention 3: Vehicle of ADX-102 Ophthalmic Drops
Intervention descriptions: intervention 1: ADX-102 Ophthalmic Drops (0.5%) administered twice in two weeks. intervention 2: ADX-102 Ophthalmic Drops (0.1%) administered twice in two weeks. intervention 3: Vehicle of ADX-102 Ophthalmic Drops administered twice in two weeks.

Protocol document:
Prot_000.pdf: 
ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
CONFIDENTIAL 
Page 1 of 56 
1 CLINICAL TRIAL PROTOCOL: ADX-102-AC-004 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Vehicle-Controlled, Phase 2b Evaluation of the Onset 
and Duration of ADX-102 Ophthalmic Drops (0.5% 
and 0.1%) Compared to Vehicle of ADX-102 
Ophthalmic Drops in the Conjunctival Allergen 
Challenge (Ora-CAC®) Model of Acute Allergic 
Conjunctivitis  
Protocol Number: 
ADX-102-AC-004 
Name of Test Drug 
/Investigational Product: 
ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 
 
Indication Studied: 
Acute allergic conjunctivitis 
Development Phase: 
2b 
Brief Description: 
Multi-center, double-masked, randomized, vehicle-
controlled, phase 2b CAC study. 
Name of Sponsor: 
 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 
Contract Research 
Organization: 
 
Ora, Inc. 
300 Brickstone Square, Third Floor 
Andover, MA 01810 
IRB/IEC: 
 
 
 
 
 
Date 
Original Protocol: 
19 October 2016 
Statement of Compliance with Good Clinical Practice 
This study will be performed in compliance with the ethical principles of the Declaration of Helsinki and the 
International Conference on Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP). 
Confidentiality Statement 
This protocol is confidential and the information available within it may not be reproduced or otherwise disseminated. 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
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TABLE OF CONTENTS 
1 CLINICAL TRIAL PROTOCOL: ADX-102-AC-004 .............................................1 
2 SYNOPSIS ....................................................................................................................3 
TABLE OF CONTENTS ..................................................................................................9 
List of Abbreviations .......................................................................................................12 
3 INTRODUCTION .......................................................................................................14 
4 STUDY OBJECTIVES..............................................................................................15 
5 CLINICAL HYPOTHESES ......................................................................................15 
6 OVERALL STUDY DESIGN ...................................................................................15 
7 STUDY POPULATION .............................................................................................15 
7.1 
Number of Subjects (approximate) ............................................................15 
7.2 
Study Population Characteristics ...............................................................16 
7.3 
inclusion Criteria .............................................................................................16 
7.4 
Exclusion Criteria ............................................................................................17 
7.5 
Withdrawal Criteria (if applicable)...............................................................18 
8 STUDY MEASURES ................................................................................................19 
8.1 
Efficacy Measures ...........................................................................................19 
8.1.1 Primary Efficacy Measure(s) ..........................................................................19 
 
8.1.3 Criteria for Effectiveness ................................................................................19 
8.2 
Safety Measures ..............................................................................................19 
9 STUDY MATERIALS................................................................................................20 
9.1 
Study Treatment(s) .........................................................................................20 
9.1.1 Study Treatment(s)/ Formulation(s) ...............................................................20 
9.1.2 Instructions for Use and Administration ........................................................20 
9.2 
Other Study Supplies .....................................................................................20 
10 STUDY METHODS AND PROCEDURES ............................................................21 
10.1 Subject Entry Procedures .............................................................................21 
10.1.1 Overview ........................................................................................................21 
10.1.2 Informed Consent ...........................................................................................21 
10.1.3 Washout Intervals ...........................................................................................21 
10.1.4 Procedures for Final Study Entry ...................................................................22 
10.1.5 Methods for Assignment to Treatment Groups: .............................................22 
10.2 Concurrent Therapies ....................................................................................22 
10.2.1 Prohibited Medications/Treatments ...............................................................23 
10.2.2 Escape Medications ........................................................................................23 
10.2.3 Special Diet or Activities ...............................................................................23 
10.3 Examination Procedures ...............................................................................23 
10.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) ....................................................................................................23 
10.4 Schedule of Visits, Measurements and Dosing ......................................28 
10.4.1 Scheduled Visits .............................................................................................28 
10.4.2 Unscheduled Visits .........................................................................................29 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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10.5 Compliance with Protocol .............................................................................29 
10.6 Subject Disposition.........................................................................................29 
10.6.1 Completed Subjects ........................................................................................29 
10.6.2 Discontinued Subjects ....................................................................................29 
10.7 Study Termination ...........................................................................................30 
10.8 STUDY Duration ...............................................................................................30 
10.9 Monitoring and Quality Assurance .............................................................30 
11 ADVERSE EVENTS .................................................................................................30 
11.1.1 Severity ...........................................................................................................31 
11.1.2 Relationship to Investigational Product .........................................................31 
11.1.3 Expectedness ..................................................................................................32 
11.2 Serious Adverse Events ................................................................................32 
11.3 Procedures for Reporting Adverse Events ..............................................33 
11.3.1 Reporting a Suspected Unexpected Adverse Reaction ..................................33 
11.3.2 Reporting a Serious Adverse Event ................................................................34 
11.4 Procedures for Unmasking (if applicable) ................................................34 
11.5 Type and Duration of the Follow-up of Subjects after Adverse 
Events .................................................................................................................34 
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ...................35 
12.1 Study Populations ...........................................................................................35 
12.1.1 Intent-to-Treat Population ..............................................................................35 
12.1.2 Per-Protocol Population .................................................................................35 
12.1.3 Safety Population ...........................................................................................35 
12.2 General Imputation Methods ........................................................................35 
12.3 Primary Efficacy Variables ............................................................................36 
12.4 Criteria for Efficacy .........................................................................................36 
 
12.6 Statistical Hypotheses ...................................................................................37 
12.7 Sample Size ......................................................................................................37 
12.8 Demographic and Baseline Medical History ............................................37 
12.9 Primary Efficacy Analyses ............................................................................37 
 
12.11 Adjustment for Multiplicity ...........................................................................38 
12.12 Safety Analysis ................................................................................................38 
12.13 Interim Analysis ...............................................................................................39 
13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES....................................39 
13.1 Protection of Human Subjects .....................................................................39 
13.1.1 Subject Informed Consent ..............................................................................39 
13.1.2 Institutional Review Board (IRB) Approval ..................................................40 
13.2 Ethical Conduct of the Study .......................................................................40 
13.3 Subject Confidentiality ..................................................................................40 
13.4 Documentation .................................................................................................40 
13.4.1 Retention of Documentation ..........................................................................40 


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Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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13.5 Labeling, Packaging, Storage, Accountability, and Return or 
Disposal of Investigational Product ...........................................................41 
13.5.1 Labeling/Packaging ........................................................................................41 
13.5.2 Storage of Investigational Product .................................................................41 
13.5.3 Accountability of Investigational Product ......................................................42 
13.5.4 Final accountability and Disposal of Investigational Product ........................42 
13.6 Recording of Data on Source Documents and Case Reports Forms 
(CRFs) .................................................................................................................42 
13.7 Handling of Biological Specimens .............................................................42 
13.8 Publications ......................................................................................................42 
14 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 .............................50 
Appendix 4:  Handling of Biological Specimens ..................................................52 
Appendix 5:  Protocol Amendment Summary .......................................................53 
Appendix 6:  Ora Approvals .......................................................................................54 
Appendix 6:  Sponsor (Aldeyra) Approvals ...........................................................55 
Appendix 7:  Investigator’s Signature .....................................................................56 


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Clinical Trial Protocol ADX-102-AC-004 
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LIST OF ABBREVIATIONS 
AC 
allergic conjunctivitis  
ADE 
adverse device effect 
AE 
adverse event 
ANCOVA 
analysis of covariance  
BOCF 
baseline observation carried forward 
CAC 
conjunctival allergen challenge 
CFR 
Code of Federal Regulations 
CI 
confidence interval  
CRF 
case report form 
CRO 
contract research organization 
DHHS 
Department of Health and Human Services 
ECG 
electrocardiogram 
ERC 
ethical review committee 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
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 
LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 


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Clinical Trial Protocol ADX-102-AC-004 
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LS 
least squares 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation  
mmHg 
millimeters of mercury  
NCS 
not clinically significant 
NDA 
new drug application 
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
Ora-CAC® 
conjunctival allergen challenge 
OS 
left eye 
OU 
both eyes 
OTC 
over the counter 
PHI 
protected health information 
PP 
per protocol 
ROPI 
Report of Prior Investigations  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TEAE 
treatment emergent adverse event 
VA 
visual acuity 
 
 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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3 INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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4 STUDY OBJECTIVES 
To evaluate the efficacy of ADX-102 ophthalmic drops (0.5% and 0.1%) compared to 
vehicle of ADX-102 ophthalmic drops for the treatment of the signs and symptoms of 
acute allergic conjunctivitis.  
5 CLINICAL HYPOTHESES 
It is hypothesized that at least one concentration of ADX-102 ophthalmic drops will be 
more effective than vehicle of ADX-102 in the treatment of the signs and symptoms of 
acute allergic conjunctivitis.  
6 OVERALL STUDY DESIGN 
This is a multi-center, double-masked, randomized, vehicle-controlled, phase 2b study 
evaluating the efficacy of ADX-102 ophthalmic drops (0.5% and 0.1%) compared to 
vehicle of ADX-102 ophthalmic drops for the treatment of the signs and symptoms of 
acute allergic conjunctivitis.  
The trial will comprise of 4 office visits over a period of approximately 5 weeks.  Visits 1 
and 2 will be used to select a subject population that responds reproducibly to two CACs 
administered approximately 7 days apart.  Subjects who meet the entry criteria for itching 
and redness response to CAC at Visits 1 and 2 will be randomized (1:1:1) at Visit 3 (Day 
1, Enrollment/Randomization) to receive either ADX-102 ophthalmic drops (0.5%), 
ADX-102 ophthalmic drops (0.1%), or vehicle of ADX-102 ophthalmic drops bilaterally.  
Subjects will undergo the 1-hour (+5 minutes) duration of action CAC from the time of 
their instillation. Subjects will return approximately 14 days later for Visit 4 (Day 15± 3, 
10-Minutes Onset of Action CAC), at which time they will be treated with the same 
treatment they received at Visit 3 and challenged approximately 10 minutes after dosing.  
At Visit 4, final exit procedures will also be conducted and subjects will exit the study.   
7 STUDY POPULATION 
 NUMBER OF SUBJECTS (APPROXIMATE) 
7.1
Approximately 375 subjects will be screened in order to enroll approximately 150 
subjects at up to 5 sites.  




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Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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 EXCLUSION CRITERIA 
7.4
Each subject may not: 
1) have known contraindications or sensitivities to the use of the investigational 
product or any of its components;  
2) have any ocular condition that, in the opinion of the investigator, could affect the 
subject’s safety or trial parameters (including but not limited to narrow angle 
glaucoma, clinically significant blepharitis, follicular conjunctivitis, iritis, 
pterygium or a diagnosis of dry eye);   
3) have had ocular surgical intervention within three (3) months prior to Visit 1 or 
during the study and/or a history of refractive surgery within the past six (6) 
months; 
4) have a known history of retinal detachment, diabetic retinopathy, or active retinal 
disease; 
5) have the presence of an active ocular infection (bacterial, viral or fungal) or positive 
history of an ocular herpetic infection at any visit; 
6) use any of the following disallowed medications during the period indicated prior 
to Visit 1 and during the study:     
72 hours 
• systemic or ocular H1 antihistamine, H1 antihistamine/mast cell stabilizers, H1 
antihistamine- vasoconstrictor drug combinations 
7 days 
• decongestants 
• monoamine oxidase inhibitors 
• all other topical ophthalmic preparations (including artificial tears) 
• lid scrubs 
• topical prostaglandins or prostaglandin derivatives 
• ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs) 
14 days 
• inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers 
45 days 
• depo-corticosteroids 
2 months 
• immunotherapeutic agents: treatment must have been maintained steadily for at 
least 2 months; neither the immunotherapeutic agent nor its dosage may change 
during the clinical trial. 
Note: Currently marketed over-the-counter anti-allergy eye drops (i.e. anti-histamine/ vasoconstrictor 
combination products such as Visine®-A®) may be administered by trained study personnel to subjects 
at the end of Visits 1, 2, 3, and 4, after all evaluations are completed. 
7) have any significant illness (e.g. any autoimmune disease requiring therapy, severe 
cardiovascular disease [including arrhythmias] the investigator feels could be 
expected to interfere with the subject’s health or with the study parameters and/or put 




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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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8 STUDY MEASURES 
 EFFICACY MEASURES  
8.1
 Primary Efficacy Measure(s) 
8.1.1
• Ocular itching evaluated by the subject at 10(±1), 15(±1), 20(±1) minutes post-
CAC at Visits 3 and 4 (0-4 scale, allowing half unit increments) 
 Criteria for Effectiveness 
8.1.3
To demonstrate the clinical effectiveness for ocular itching, ADX-102 Ophthalmic Drops 
will need to show clinical superiority over vehicle by at least 0.5 units of a 5 point scale 
for the 10(±1), 15(±1) and 20(±1) minutes post-CAC time points within a visit, and at 
least 1 unit for the majority
 of the same three post-CAC time points within a visit for 
each treatment comparison.  
 
 SAFETY MEASURES 
8.2
• Adverse Events (reported, elicited and observed) 
• Visual Acuity at Distance Utilizing an ETDRS chart  
• Slit-lamp Biomicroscopy  
• Intraocular Pressure  
• Dilated Fundoscopy 
 




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Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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10 STUDY METHODS AND PROCEDURES 
 SUBJECT ENTRY PROCEDURES 
10.1
 Overview 
10.1.1
Subjects as defined by the criteria in section 7.2, 7.3, and 7.4 will be considered for entry 
into this study. 
 Informed Consent 
10.1.2
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed 
consent form (ICF).  The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board. Failure 
to obtain a signed ICF renders the subject ineligible for the study.   
Informed consent may be obtained within 30 days prior to Visit 1; however, informed 
consent must be obtained prior to Visit 1 if any of the following criteria are determined 
during the telephone screening process: 
• Washout of certain medications is necessary 
• Sufficient time of discontinuation of contact lens wear is necessary 
• Post-operative period 
Medical/medication history, demographics, skin test and inclusion/exclusion review may 
be performed at the time of informed consent signing prior to Visit 1, but must be 
confirmed at Visit 1 (with the exception of demographics and skin test).   
 Washout Intervals 
10.1.3
Prior to performing other study procedures at Visit 1, study staff will confirm that the 
subject has not used any of the following restricted products: 
     
72 hours 
• Contact lenses 
• systemic or ocular H1 antihistamine, H1 antihistamine/mast cell stabilizers, 
H1 antihistamine- vasoconstrictor drug combinations 
7 days 
• decongestants 
• monoamine oxidase inhibitors 
• all other topical ophthalmic preparations (including artificial tears) 
• lid scrubs 
• topical prostaglandins or prostaglandin derivatives 
• ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs) 
14 days 
• inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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45 days 
• depo-corticosteroids 
2 months 
• immunotherapeutic agents: treatment must have been maintained steadily 
for at least 2 months; neither the immunotherapeutic agent nor its dosage 
may change during the clinical trial. 
Note: 
Currently 
marketed 
over-the-counter 
anti-allergy 
eye 
drops 
(ie, 
anti-
histamine/vasoconstrictor combination products such as  Visine®-A®) may be administered by 
trained study personnel to subjects at the end of Visits 1, 2, 3, and 4, after all evaluations are 
completed. 
 
 Procedures for Final Study Entry 
10.1.4
Subjects must continue to meet all of the inclusion criteria and none of the exclusion 
criteria prior to Visit 3 to be enrolled in the study. 
 Methods for Assignment to Treatment Groups: 
10.1.5
All subjects screened for the study who sign an ICF 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 treatment and time point, to increase the 
likelihood that known and unknown subject attributes (e.g., demographics and baseline 
characteristics) are evenly balanced across treatment groups and across time points, and 
to enhance the validity of statistical comparisons.  
Once a subject meets all qualification criteria at Visit 3 (Day 1), they will be enrolled and 
randomly assigned to masked treatment using a 1:1:1 (ADX-102 ophthalmic drops 
[0.5%]: ADX-102 ophthalmic drops [0.1%]: vehicle of ADX-102 ophthalmic drops) 
assignment ratio.  Subjects will be assigned the lowest 4-digit randomization number 
available at the Investigative site within the appropriate stratum.  The randomization 
number will be stratified by the average post-CAC itching scores 
 at 
baseline (Visit 2) to ensure balance for the primary endpoint of ocular itching.  No 
randomization numbers will be skipped or omitted.  
 
 CONCURRENT THERAPIES 
10.2
 
 
 
 
 


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Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
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 Prohibited Medications/Treatments 
10.2.1
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Escape Medications 
10.2.2
 
 
 Special Diet or Activities 
10.2.3
Not Applicable. 
 EXAMINATION PROCEDURES 
10.3
The following procedures will be conducted as listed in Section 10.3.1. 
 Procedures to be Performed at Each Study Visit with Regard to Study 
10.3.1
Objective(s) 
10.3.1.1 
VISIT 1 (Day -21±3): Screening /Titration CAC 
• Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment 
and/or study visit procedures, the study will be discussed with each subject and 
subjects wishing to participate must give written informed consent and sign a HIPAA 
form. 












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Clinical Trial Protocol ADX-102-AC-004 
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If a subject is discontinued at a scheduled study visit, the remaining assessments should 
be captured on the Unscheduled Visit/Early Exit Visit pages of the source document and 
corresponding eCRF. 
 Unscheduled Visits 
10.4.2
For Unscheduled Visits, the reason for the visit should be clearly documented on the 
appropriate eCRF, including findings from all evaluations that are completed.  
These visits may be performed to ensure subject safety.  All information gathered at 
unscheduled visits should be recorded on the Unscheduled Visit/Early Exit Visit pages of 
the source document and corresponding eCRF. 
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 Utilizing an ETDRS chart 
• Slit-lamp Biomicroscopy 
• Intraocular Pressure  
• Dilated Fundoscopy  
• Assessment of Adverse Events  
 COMPLIANCE WITH PROTOCOL 
10.5
Site staff will review concomitant medication use at each visit.  
Subjects who are inappropriately enrolled will be discontinued from the study. The 
reason for such discontinuation will be recorded as “protocol violation” in the source 
document and on the appropriate page in the eCRF.  
 SUBJECT DISPOSITION 
10.6
 Completed Subjects 
10.6.1
A completed subject is one who has not been discontinued from the study. 
 Discontinued Subjects 
10.6.2
Subjects may be discontinued prior to their completion of the study due to: 
• adverse events 
• protocol violations 
• lack of efficacy 
• administrative reasons (eg, inability to continue, lost to follow up) 


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Clinical Trial Protocol ADX-102-AC-004 
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• manifest clinically active signs or symptoms of allergic conjunctivitis 
during the pre-CAC ocular allergic signs & symptoms assessment at 
Visit 4 
• Sponsor termination of study 
• other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or study Sponsor and will be clearly documented on the eCRF. 
 STUDY TERMINATION 
10.7
The study may be stopped at any time by the investigator, the Sponsor, and/or Ora with 
appropriate notification. 
 STUDY DURATION 
10.8
Four office visits over a period of approximately 5 weeks. 
 MONITORING AND QUALITY ASSURANCE 
10.9
During the course of the study an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess study drug accountability, and ensure the study is 
being conducted according to the pertinent regulatory requirements.  The review of the 
subjects’ medical records will be performed in a manner that adequately maintains 
subject confidentiality.  Further details of the study monitoring will be outlined in a 
monitoring plan. 
Regulatory authorities of domestic and foreign agencies, Ora quality assurance and/or its 
designees, as well as the Sponsor, may carry out on-site inspections and/or audits which 
may include source data checks.  Therefore, direct access to the original source data will 
be required for inspections and/or audits.  All inspections and audits will be carried out 
giving consideration to data protection as well as subject confidentiality to the extent that 
local, state, and federal laws apply. 
11 ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence associated with the use of an 
investigational product (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 


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Clinical Trial Protocol ADX-102-AC-004 
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impact medical device performance (e.g., anatomical limitations), and therapeutic 
parameters (e.g., energy applied, sizing, dose release) associated with medical device. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the 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 1 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 study. 
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 
11.1.1
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 
11.1.2
The relationship of each adverse event to the investigational product should be 
determined by the investigator using these explanations: 
• Suspected:  A reasonable possibility exists that the investigational product caused the 
adverse event. 
• Not Suspected: A reasonable possibility does not exist that the investigational product 
caused the adverse event. 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
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Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the investigational product caused the adverse event.  “Reasonable 
possibility” means there is evidence to suggest a causal relationship between the 
investigational product and the adverse event.  Types of evidence that would suggest a 
causal relationship between the investigational product and the adverse event include:  a 
single occurrence of an event that is uncommon and known to be strongly associated with 
investigational product exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome); one or more occurrences of an event that is not commonly associated with 
investigational product exposure, but is otherwise uncommon in the population exposed 
to the investigational product (eg, tendon rupture); an aggregate analysis of specific 
events observed in a clinical trial (such as known consequences of the underlying disease 
or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more 
frequently in the investigational product-treatment group than in a concurrent or 
historical control group. 
 Expectedness 
11.1.3
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
• Unexpected:  an AE that is not listed in the Investigator’s Brochure (IB) or Report of 
Prior Investigations (ROPI) or is not listed at the specificity or severity that has been 
observed. 
• Expected:  an AE that is listed in the IB or ROPI at the specificity and severity that 
has been observed. 
• Not applicable: an AE unrelated to the IP. 
AEs that are mentioned in the IB or ROPI 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 
11.2
An AE is considered serious if, in the view of either the investigator or Sponsor/designee, 
it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 33 of 56 
Note:  An AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor/designee, its occurrence places the subject at immediate 
risk of death.  It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note:  The term “inpatient hospitalization” refers to any inpatient admission (even 
if less than 24 hours).  For chronic or long-term inpatients, inpatient admission 
includes transfer within the hospital to an acute/intensive care inpatient unit.  
Inpatient hospitalization does not include:  emergency room visits; 
outpatient/same-day/ambulatory procedures; observation/short stay units; 
rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
Note:  The term “prolongation of existing hospitalization” refers to any extension 
of an inpatient hospitalization beyond the stay anticipated or required for the 
reason for the initial admission as determined by the investigator or treating 
physician. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
Note:  A serious adverse event (SAE) specifically related to visual threat would 
be interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 PROCEDURES FOR REPORTING ADVERSE EVENTS 
11.3
All AEs and their outcomes must be reported to Ora, the study 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 
11.3.1
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the study 
Sponsor/designee and the IRB/IEC as required by the IRB/IEC, federal, state, or local 
regulations and governing health authorities. 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 34 of 56 
 Reporting a Serious Adverse Event 
11.3.2
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 case report form.  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 case report form.  All subjects experiencing a SAE must be followed up 
and the outcome reported. 
In the event of a SAE, the investigator must immediately notify the appropriate contact 
in the Study Manual.  
In addition, the investigator must obtain and maintain in his/her files all pertinent medical 
records, information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject; provide 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 within their guidelines for reporting SAEs.  
 PROCEDURES FOR UNMASKING (IF APPLICABLE) 
11.4
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 
discuss the subject’s emergency situation and the need to unmask a study subject prior to 
unmasking IP.   
If the investigator determines that emergency unmasking is necessary, the investigator 
should identify the given subject’s study 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.   
Subjects will have the IP treatment discontinued immediately if treatment assignment is 
unmasked and will be discontinued from the study.  
 
 TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS 
11.5
AFTER ADVERSE EVENTS 
AEs will be followed until:  
• Resolution (return to baseline status or to ‘normal’) 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 35 of 56 
• Stabilization of the event has occurred (no worsening or improvement expected by 
the Investigator) 
• Event is otherwise explained, regardless of whether the subject is still participating in 
the study 
If the subject is lost to follow-up, the investigator should make 3 reasonable attempts to 
contact the subject via telephone, post, or certified mail. All follow-up will be 
documented in the subject’s source document. Non-serious adverse events identified on 
the last scheduled contact must be recorded on the AE CRF with the status noted.  
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 STUDY POPULATIONS 
12.1
 Intent-to-Treat Population 
12.1.1
The Intent-to-Treat (ITT) population consists of all subjects who are randomized.  All 
data will be included and no subjects will be excluded because of protocol violations.  
The ITT population will be analyzed as randomized and will be used for the efficacy 
analyses.  
 Per-Protocol Population 
12.1.2
The Per-Protocol (PP) population is a subset of the ITT population and includes the 
subjects who completed the study through Visit 4 (Day 15) with no major protocol 
violations. This population will be analyzed as treated using observed data only for 
confirmatory analyses. 
 Safety Population 
12.1.3
The safety population includes all randomized subjects who received the test article. The 
safety population will be analyzed as treated and will be used for the safety analyses. No 
data will be excluded for any reason. 
 GENERAL IMPUTATION METHODS 
12.2
 
 
 
 
   


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 36 of 56 
 
 
 
 
 PRIMARY EFFICACY VARIABLES 
12.3
The primary efficacy variable is: 
• Ocular itching evaluated by the subject at 10(±1), 15(±1), and 20(±1) minutes post-
CAC at Visits 3 and 4 (0-4 scale, allowing half unit increments). 
 CRITERIA FOR EFFICACY  
12.4
This clinical study is designed to evaluate the efficacy of ADX-102 Ophthalmic Drops 
compared to vehicle in the prevention of ocular itching at each designated time point 
post-CAC at Visits 3 and 4.  
To demonstrate the clinical effectiveness for ocular itching, ADX-102 Ophthalmic Drops 
will need to show clinical superiority over vehicle by at least 0.5 units of a 5 point scale 
for the 10(±1), 15(±1) and 20(±1) minutes post-CAC time points within a visit, and at 
least 1 unit for the majority 
 of the same three post-CAC time points within a visit for 
each treatment comparison. ADX-102 Ophthalmic Drops will also need to show 
statistical superiority over vehicle at each of the three time points.  The treatments will be 
tested against vehicle hierarchically, with the higher dose (0.5% ADX-102 Ophthalmic 
Drops) tested first and the lower dose (0.1% ADX-102 Ophthalmic Drops) tested 
conditional upon the higher dose showing statistical significance over vehicle. 




ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 38 of 56 
 ADJUSTMENT FOR MULTIPLICITY 
12.11
 
 
 
 
 
 
 
 
 
 
 
 
 
 SAFETY ANALYSIS 
12.12
The primary safety variable is the incidence of subjects with any adverse event during the 
entire study.  The percentage of subjects with specific treatment-emergent adverse events 
(TEAEs) will be summarized for each treatment group.  Incidence will be tabulated by 
MedDRA System Organ Class and preferred term within each system organ class.  
Adverse events will also be summarized for treatment-related AEs, SAEs, by maximal 
severity, and by day of onset relative to the start of treatment. 
The secondary safety variables of slit lamp biomicroscopy, dilated fundus examination, 
visual acuity, and IOP will be summarized descriptively using quantitative and qualitative 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 39 of 56 
summary statistics as appropriate.  Changes and shifts from baseline will also be 
summarized where applicable. 
 INTERIM ANALYSIS 
12.13
No interim analyses are planned. 
13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonization (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 investigational 
products in the countries involved will be adhered to. 
 PROTECTION OF HUMAN SUBJECTS 
13.1
 Subject Informed Consent 
13.1.1
Informed consent must take place before any study specific procedures are initiated.  
Signed and dated written informed consent must be obtained from each subject and/or 
from the subject’s parent or legal guardian prior to enrollment into the study.   
All informed consent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use.  If the consent form 
requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 
and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
Informed consent may be obtained within 30 days prior to Visit 1, however, informed 
consent must be obtained prior to Visit 1 if any of the following criteria are determined 
during the telephone screening process: 
• Proper washout of certain medications is necessary 
• Sufficient time of discontinuation of contact lens wear is necessary 
• Post-operative period 
Medical/medication history, demographics, skin test and inclusion/exclusion review may 
be performed at the time of informed consent signing prior to Visit 1, but must be 
confirmed at Visit 1 (with the exception of demographics and skin test).   


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 40 of 56 
 Institutional Review Board (IRB) Approval 
13.1.2
This study is to be conducted in accordance with Institutional Review Board regulations 
(U.S. 21 CFR Part 56.103).  The investigator must obtain appropriate IRB approval 
before initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
 ETHICAL CONDUCT OF THE STUDY 
13.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 SUBJECT CONFIDENTIALITY 
13.3
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data in accordance with local, state, and federal laws 
and regulations. 
Monitors, auditors and other authorized representatives of Ora, the Sponsor, the IRB/IEC 
approving this study, the Food and Drug Administration, the Department of Health and 
Human Services, other domestic government agencies, and other foreign regulatory 
agencies will be granted direct access to the study subject’s original medical and study 
records for verification of the data and/or clinical trial procedures.  Access to this 
information will be permitted to the aforementioned individuals to the extent permitted 
by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the investigational product may ultimately be 
marketed, but the subject’s identity will not be disclosed in these documents. 
 DOCUMENTATION 
13.4
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and electrocardiograms.  The investigator’s copy of the eCRFs 
serves as the investigator’s record of a subject’s study-related data. 
 Retention of Documentation 
13.4.1
All study related correspondence, subject records, ICFs, record of the distribution and use 
of all IPs and copies of eCRFs should be maintained on file for at least 2 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 2 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 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 41 of 56 
to inform the investigator/institution as to when these documents no longer need to be 
retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility.  The Sponsor must be notified in writing of the name and 
address of the new custodian. 
 LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, AND 
13.5
RETURN OR DISPOSAL OF INVESTIGATIONAL PRODUCT 
 Labeling/Packaging 
13.5.1
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 Storage of Investigational Product 
13.5.2
  
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 study, in 
accordance with the conditions specified in this protocol. 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 42 of 56 
 Accountability of Investigational Product 
13.5.3
The IP is to only be prescribed by the principal investigator or his/her named sub 
investigator(s), and is to only be used in accordance with this protocol.  The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study.  A detailed inventory must be completed for the IP and available for Sponsor’s 
review during the course of the study. 
 Final accountability and Disposal of Investigational Product 
13.5.4
At the conclusion of the study, all IP reconciliation will be performed and all remaining 
IP will be destructed and disposed according to clinical site’s SOP. Sponsor will be 
provided with a final accounting of study drug for approval prior to destruction.  
 RECORDING OF DATA ON SOURCE DOCUMENTS AND CASE 
13.6
REPORTS FORMS (CRFS) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF, source document, and all study-related material.  All 
study data should also be attributable, legible, contemporaneous, and original.  Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data).  An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
 HANDLING OF BIOLOGICAL SPECIMENS 
13.7
Not Applicable. 
 PUBLICATIONS 
13.8
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study.  Authorship will be established before writing the manuscript.  Ora 
and the study Sponsor will have the final decision regarding the manuscript and 
publication. 
 
 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 43 of 56 
14 REFERENCES 
  
 
 
  
 
 
 
 
 
 
















ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 51 of 56 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 


ADX-102 Ophthalmic Drops (0.5% and 0.1%) 
 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 52 of 56 
APPENDIX 4:  HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 


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 Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-AC-004 
Final 1.0, 19 October 2016 
 
Confidential 
Page 53 of 56 
APPENDIX 5:  PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 











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