Conditions: Dry Eye Syndromes
Keywords: Aldeyra
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
The objective of this study is to evaluate the safety, tolerability, and pharmacodynamic activity of ADX-102 Ophthalmic Solutions and ADX-102 Ophthalmic Lipid Solution in subjects with dry eye syndrome.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: ADX-102 Ophthalmic Solution (0.5%) intervention 2: ADX-102 Ophthalmic Solution (0.1%) intervention 3: ADX-102 Ophthalmic Lipid Solution (0.5%)
Intervention descriptions: intervention 1: ADX-102 Ophthalmic Solution (0.5%) administered for approximately 4 weeks. intervention 2: ADX-102 Ophthalmic Solution (0.1%) administered for approximately 4 weeks. intervention 3: ADX-102 Ophthalmic Lipid Solution administered for approximately 4 weeks.

Protocol document:
Prot_002.pdf: 
Aldeyra Therapeutics, Inc. 
Clinical Trial Protocol ADX-102-DES-007 
Final V1.0 27Mar2017 
Confidential 
Page 1 of 67 
Clinical Trial Protocol 
Protocol Title: 
A Single-Center, Phase 2a, Randomized, 
Double-Masked, Clinical Study to Assess the Safety, 
Tolerability, and Pharmacodynamic Activity of 
ADX-102 Ophthalmic Solution in Subjects with Dry 
Eye Syndrome  
Protocol Number: 
ADX-102-DES-007 
Study Phase: 
2a 
Product Name: 
ADX-102 Ophthalmic Solution (0.5% and 0.1%) 
 
 
Indication: 
Dry Eye Syndrome (DES) 
Sponsor: 
Aldeyra Therapeutics, Inc. 
131 Hartwell Ave. 
Lexington, MA 02421 USA 
Contract Research 
Organization: 
Ora. Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 USA 
 
 
 
 
 
Date 
Original Protocol: 
27 March 2017 
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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SYNOPSIS 
Protocol Title: 
A Single-Center, Phase 2a, Randomized, 
Double-Masked, Clinical Study to Assess the Safety, 
Tolerability, and Pharmacodynamic Activity of ADX-
102 Ophthalmic Solution in Subjects with Dry Eye 
Syndrome  
Protocol Number: 
ADX-102-DES-007 
Study Drug: 
1) ADX-102 Ophthalmic Solution (0.5%)
2) ADX-102 Ophthalmic Solution (0.1%)
3) ADX-102 Ophthalmic Lipid Solution (0.5%)
Study Phase: 
2a 
Study Objective: 
The objective of this study is to evaluate the safety, 
tolerability, and pharmacodynamic activity of ADX-102 
Ophthalmic Solutions and ADX-102 Ophthalmic Lipid 
Solution in subjects with dry eye syndrome. 
Overall Study Design 
Structure: 
Single-center, double-masked, randomized study 
Duration: 
An individual subject’s participation is estimated to be 
approximately 4 weeks (28 days). 
Dosage/Dose Regimen: 
Subjects eligible to be randomized will receive one of 
the following treatments to be administered bilaterally 
four times daily (QID) for 28 days (from Visit 1 to Visit 
3). 
1) ADX-102 Ophthalmic Solution (0.5%)
2) ADX-102 Ophthalmic Solution (0.1%)
3) ADX-102 Ophthalmic Lipid Solution (0.5%)
Summary of Visit 
Schedule: 
3 visits over the course of approximately 4 weeks 

Visit 1 = Day 1, Screening and Enrollment

Visit 2 = Day 8 ± 1, 1-Week Follow-Up

Visit 3 = Day 29 ± 2, 4-Week Follow-Up
Measures Taken to 
Reduce Bias: 
This is a randomized treatment assignment, 
double-masked study. 
Study Population 
Characteristics 
Number of Subjects: 
Approximately 60 subjects will be screened to enroll 45 
subjects (15 per treatment arm). 
Condition/Disease: 
Dry Eye Syndrome (DES) 


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Final V1.0 27Mar2017 
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Inclusion Criteria: 
Subjects must: 
1. Be at least 18 years of age of either gender and any
race;
2. Provide written informed consent and sign the
Health Information Portability and Accountability
Act (HIPAA) form;
3. Have a reported history of dry eye for at least
 prior to Visit 1; 
4. Have a history of use or desire to use eye drops for
dry eye symptoms within 
 of Visit 1; 
5. Report a score of
 on the Ora Calibra® Ocular 
Discomfort & 4-symptom questionnaire in at least 
one symptom at Visit 1; 
6. Have a Schirmer’s Test score of
 at Visit 1; 
7. Have a tear film break-up time (TFBUT©)
 at Visit 1; 
8. Have a corneal fluorescein staining score of 
 in
at least one region (e.g. inferior, superior, or central)
at Visit 1;
9. Have a sum corneal fluorescein staining score of
, based on the sum of the inferior, superior, and
central regions, at Visit 1;
10. Have a total lissamine green conjunctival score of
, based on the sum of the temporal and nasal
regions at Visit 1;
11. Have at least one eye satisfy all criteria for 6, 7, 8,
9, and 10 above.
Exclusion Criteria: 
Subjects must not: 
1. Have any clinically significant slit lamp findings at
Visit 1 that may include active blepharitis,
meibomian gland dysfunction (MGD), lid margin
inflammation, or active ocular allergies that require
therapeutic treatment, and/or in the opinion of the
investigator may interfere with study parameters;


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Final V1.0 27Mar2017 
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2. Be diagnosed with an ongoing ocular infection
(bacterial, viral, or fungal), or active ocular
inflammation at Visit 1;
3. Have worn contact lenses within 7 days of Visit 1 or
anticipate using contact lenses during the study;
4. Have used any eye drops within 2 hours of Visit 1;
5. Have previously had laser-assisted in situ
keratomileusis (LASIK) surgery within the last 12
months;
6. Have used cyclosporine 0.05% or lifitigrast 5.0%
ophthalmic solution within 45 days of Visit 1;
7. Have any planned ocular and/or lid surgeries over
the study period or any ocular surgery within the
last 6 months;
8. Be using or anticipate using temporary punctal
plugs during the study that have not been stable
within 30 days of Visit 1;
9. Be currently taking any topical ophthalmic
prescription (including medications for glaucoma)
or over-the-counter (OTC) solutions, artificial tears,
gels or scrubs, and cannot discontinue these
medications for the duration of the trial (excluding
medications allowed for the conduct of the study);
10. Have corrected visual acuity greater than or equal to
logarithm of the minimum angle of resolution
(logMAR) + 0.7 as assessed by Early Treatment of
Diabetic Retinopathy Study (ETDRS) scale in both
eyes at Visit 1;
11. Be a woman who is pregnant, nursing, or planning a
pregnancy;
12. Be unwilling to submit a urine pregnancy test at
Visit 1 and Visit 3 (or early termination visit) if of
childbearing potential.  Non-childbearing potential
is defined as a woman who is permanently sterilized
(e.g., has had a hysterectomy or tubal ligation), or is
post-menopausal (without menses for
12 consecutive months);


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13. Be a man or woman of childbearing potential who is
not using an acceptable means of birth control;
acceptable methods of contraception include:
hormonal – oral, implantable, injectable, or
transdermal contraceptives; mechanical –
spermicide in conjunction with a barrier such as a
diaphragm or condom; intrauterine device (IUD); or
surgical sterilization of partner.  For non-sexually
active males or females, abstinence may be regarded
as an adequate method of birth control; however, if
the subject becomes sexually active during the
study, he/she must agree to use adequate birth
control as defined above for the remainder of the
study;
14. Have a known allergy and/or sensitivity to the test
article or its components;
15. Have a condition or be in a situation which the
investigator feels may put the subject at significant
risk, may confound the study results, or may
interfere significantly with the subject’s
participation in the study;
16. Be currently enrolled in an investigational drug or
device study or have used an investigational drug or
device within 30 days of Visit 1;
17. Have previously used ADX-102 ophthalmic
solution;
18. Be currently using any medication known to cause
ocular drying that is not used on a stable dosing
regimen for at least 30 days prior to Visit 1;
19. Be unable or unwilling to follow instructions,
including participation in all study assessments and
visits.
Study Formulations: 

ADX-102 Ophthalmic Solution (0.5%)

ADX-102 Ophthalmic Solution (0.1%)

ADX-102 Ophthalmic Lipid Solution (0.5%)


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Evaluation Criteria 
Safety Measures: 

Visual acuity

Slit-lamp evaluation

Adverse event query

Intraocular Pressure (IOP)

Undilated fundoscopy
Exploratory 
Pharmocodynamic 
Measures: 

Ora CalibraTM Drop Comfort assessment;
 
 
 
 
 
 
Other: 
Not applicable. 
General Statistical Methods and Types of Analyses 
Analysis Populations 

Intent-to-Treat Population – The intent-to-treat (ITT) population includes all
randomized subjects.  Subjects in the ITT population will be analyzed as
randomized.

Per-Protocol Population – The per-protocol (PP) population includes subjects
in the ITT population who do not have significant protocol deviations and
who complete the study.  Protocol deviations will be assessed prior to
database lock and unmasking.  Subjects in the PP population will be
analyzed as treated.

Safety Population – The safety population includes all randomized subjects
who have received at least one dose of the investigational product.  Subjects
in the Safety population will be analyzed as treated.


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Primary Efficacy Analyses: 
There are no primary endpoints in this Phase 2a study. 
Secondary Efficacy Analyses: 
There are no secondary endpoints in this Phase 2a study. 
Safety Variables: 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies 
and percentages of subjects with treatment-emergent adverse events (TEAEs), 
serious TEAEs, and TEAEs causing premature discontinuation will be provided 
by treatment group. An AE is treatment emergent if it occurs or worsens after the 
first dose of study treatment. Furthermore, frequencies will be given of subjects 
with TEAEs by system organ class, by system organ class and preferred term, by 
system organ class, preferred term and maximal severity, by system organ class, 
preferred term and strongest relationship, and by system organ class, preferred 
term, maximal severity, and strongest relationship. Separate summaries will be 
performed for ocular and non-ocular AEs.  
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, 
undilated fundoscopy, and intraocular pressure will be summarized by treatment 
group and visit using descriptive statistics. Changes or shifts from baseline will 
also be summarized where appropriate. For assessments performed by eye, study 
eye and fellow eye will be summarized separately.  
 
 
 
 
 
  


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Summary of Known and Potential Risks and Benefits to Human Subjects 
Refer to Investigator’s Brochure. 


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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ................................................................................................10 
LIST OF ABBREVIATIONS .........................................................................................13 
1 
INTRODUCTION...................................................................................................15 
2 
CLINICAL STUDIES OF ADX-102 OPHTHALMIC SOLUTION..................16 
2.1 
Phase 1 Clinical Trial ...................................................................................16 
2.2 
Phase 2 Clinical Trial of ADX-102 in Allergic Conjunctivitis ..................16 
2.3 
Phase 2 Clinical Trial of ADX-102 in Non-infectious Anterior Uveitis ...17 
2.4 
Minimization of Risk ....................................................................................17 
3 
STUDY OBJECTIVES ...........................................................................................18 
4 
DESIGN ...................................................................................................................18 
5 
STUDY POPULATION .........................................................................................19 
5.1 
Number of Subjects ......................................................................................19 
5.2 
Study Population Characteristics ...............................................................20 
5.3 
Inclusion Criteria .........................................................................................20 
5.4 
Exclusion Criteria .........................................................................................20 
5.5 
Withdrawal Criteria (if applicable) ............................................................22 
6 
STUDY PARAMETERS ........................................................................................22 
6.1 
Efficacy Measures .........................................................................................22 
 
 
6.2 
Safety Measures ............................................................................................23 
7 
STUDY MATERIALS ............................................................................................23 
7.1 
Study Drug(s) ................................................................................................23 
7.1.1 
Formulations .....................................................................................23 
7.1.2 
Dispensation Schedule ......................................................................23 
7.1.3 
Instructions for Use ...........................................................................23 
7.2 
Other Study Supplies ...................................................................................24 
8 
STUDY METHODS AND PROCEDURES .........................................................24 
8.1 
Subject Entry Procedures ............................................................................24 
8.1.1 
Overview ...........................................................................................24 
8.1.2 
Informed Consent..............................................................................24 
8.1.3 
Washout Intervals .............................................................................24 
8.1.4 
Procedures for Final Study Entry ......................................................24 
8.1.5 
Methods for Assignment to Treatment Groups ................................24 
8.2 
Concurrent Therapies ..................................................................................25 
8.2.1 
Prohibited Medications/Treatments ..................................................25 
8.2.2 
Escape Medications ..........................................................................25 
8.2.3 
Special Diet or Activities ..................................................................25 
8.3 
Examination Procedures ..............................................................................25 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ..........................................................................................25 
8.4 
Schedule of Visits, Measurements, and Dosing .........................................28 
8.4.1 
Scheduled Visits................................................................................28 
8.4.2 
Unscheduled Visits ...........................................................................28 
8.5 
Compliance with Protocol ............................................................................28 


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8.6 
Subject Disposition .......................................................................................29 
8.6.1 
Completed Subjects ..........................................................................29 
8.6.2 
Discontinued Subjects .......................................................................29 
8.7 
Study Termination .......................................................................................29 
8.8 
Study Duration .............................................................................................29 
8.9 
Monitoring and Quality Assurance ............................................................29 
9 
ADVERSE EVENTS ..............................................................................................31 
9.1 
Adverse Event ...............................................................................................31 
9.1.1 
Severity .............................................................................................31 
9.1.2 
Relationship to Study Drug ...............................................................31 
9.1.3 
Expectedness .....................................................................................32 
9.2 
Serious Adverse Events ................................................................................32 
9.3 
Procedures for Reporting Adverse Events .................................................33 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................33 
9.3.2 
Reporting a Serious Adverse Event ..................................................34 
9.4 
Procedures for Unmasking of Study Drug .................................................34 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ..35 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES................35 
10.1 Analysis Populations ....................................................................................35 
10.2 Statistical Hypotheses ...................................................................................35 
10.3 Sample Size ...................................................................................................36 
10.4 Statistical Analysis ........................................................................................36 
10.4.1 General Considerations .....................................................................36 
10.4.2 Unit of Analysis ................................................................................36 
10.4.3 Missing Data .....................................................................................37 
10.4.4 Multiplicity Consideration ................................................................37 
10.4.5 Primary Efficacy Analyses ...............................................................37 
10.4.6 Secondary Efficacy Analyses ...........................................................37 
10.4.7 Safety Variables ................................................................................37 
10.4.8 Exploratory Pharmacodynamic (Efficacy) Measures .......................37 
10.4.9 Interim Analyses ...............................................................................38 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................38 
11.1 Protection of Human Subjects.....................................................................38 
11.1.1 Subject Informed Consent.................................................................38 
11.1.2 Institutional Review Board (IRB) Approval .....................................38 
11.2 Ethical Conduct of the Study ......................................................................39 
11.3 Subject Confidentiality ................................................................................39 
11.4 Documentation ..............................................................................................39 
11.4.1 Retention of Documentation .............................................................39 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ....................................................................................................40 
11.5.1 Labeling/Packaging...........................................................................40 
11.5.2 Storage of Study Drug ......................................................................40 
11.5.3 Accountability of Study Drug ...........................................................40 
11.5.4 Return or Disposal of Study Drug ....................................................40 


 
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11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs)..............................................................................................40 
11.7 Handling of Biological Specimens ...............................................................41 
11.8 Publications ...................................................................................................41 
12 
REFERENCES ........................................................................................................42 
13 
APPENDICES .........................................................................................................44 
Appendix 1:  Schedule of Visits and Measurements ...................................................44 
Appendix 2:  Examination Procedures, Tests, Equipment, and Techniques ...........46 
Appendix 3:  Amendment Summary of Changes........................................................65 
Appendix 4:  Sponsor and Ora Approvals ..................................................................66 
Appendix 5:  Investigator’s Signature .........................................................................67 
 
 


 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DES 
Dry Eye Syndrome 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
EKG 
Electrocardiograph 
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 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IRB 
institutional/independent review board 
ITT 
intent-to-treat 
IUD 
Intra-uterine device 
IWRS 
interactive web response system 
LASIK 
laser in situ keratomileusis 
LOCF 
last observation carried forward 
LPS 
lipopolysaccharide 
logMAR 
logarithm of the minimum angle of resolution 
MDA 
Malondialdehyde; malonaldehyde 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
meibomian gland dysfunction 
mL 
Milliliter 
mm 
Millimeter 
µg  
microgram  
µL  
microliter  
µm 
Micrometer 
mmHg 
millimeters of mercury 
OD 
right eye 
OS 
left eye 
 
 
OU 
both eyes 
OTC 
over-the-counter 
PP 
per protocol 
QID 
four times a day 
SAE 
serious adverse event 


 
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TEAEs 
treatment emergent adverse events 
VA 
visual acuity 
 
 
 
 


 
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1 INTRODUCTION 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2 CLINICAL STUDIES OF ADX-102 OPHTHALMIC SOLUTION 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
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3 STUDY OBJECTIVES  
The objective of this study is to evaluate the safety, tolerability and pharmacodynamic 
activity of ADX-102 Ophthalmic Solutions (0.5% and 0.1%) and ADX-102 Ophthalmic 
Lipid Solution (0.5%) in subjects with dry eye. 
 
CLINICAL HYPOTHESIS 
 
 
  
4 DESIGN 
This is a Phase 2a, single-center, randomized, double-masked study designed to evaluate 
the safety, tolerability and pharmacodynamic activity of ADX-102 Ophthalmic Solution 
(0.5%), ADX-102 Ophthalmic Solution (0.1%), and ADX-102 Ophthalmic Lipid 
Solution (0.5%) in subjects with dry eye. Approximately 45 male and female subjects at 
least 18 years of age with a subject-reported history of dry eye in both eyes and meeting 
all other study eligibility criteria will be randomized to receive treatment ADX-102 
Ophthalmic Solution (0.5%), ADX-102 Ophthalmic Solution (0.1%), or ADX-102 
Ophthalmic Lipid Solution (0.5%) in a 1:1:1 ratio (approximately 15 subjects in each 
treatment group). 
 
 




 
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5.2 Study Population Characteristics 
All subjects must be at least 18 years of age, of either gender, and of any race, and must 
meet all inclusion criteria and none of the exclusion criteria. 
5.3 Inclusion Criteria 
Subjects must: 
 
1. Be at least 18 years of age of either gender and any race; 
 
2. Provide written informed consent and sign the Health Information Portability 
and Accountability Act (HIPAA) form; 
 
3. Have a reported history of dry eye for at least 
prior to Visit 1; 
 
4. Have a history of use or desire to use eye drops for dry eye symptoms within  
 of Visit 1; 
 
5. Report a score of 
 on the Ora Calibra® Ocular Discomfort & 4-symptom 
questionnaire in at least one symptom at Visit 1; 
 
6. Have a Schirmer’s Test score of 
 at Visit 1; 
 
7. Have a tear film break-up time (TFBUT©) 
 at Visit 1;  
 
8. Have a corneal fluorescein staining score of 
 in at least one region (e.g. 
inferior, superior, or central) at Visit 1; 
 
9. Have a sum corneal fluorescein staining score of 
 based on the sum of the 
inferior, superior, and central regions, at Visit 1;  
 
10. Have a total lissamine green conjunctival score of 
 based on the sum of the 
temporal and nasal regions at Visit 1; 
 
11. Have at least one eye satisfy all criteria for 6, 7, 8, 9, and 10 above. 
5.4 Exclusion Criteria 
Subjects must not: 
1. Have any clinically significant slit lamp findings at Visit 1 that may 
include active blepharitis, meibomian gland dysfunction (MGD), lid 
margin inflammation, or active ocular allergies that require therapeutic 
treatment, and/or in the opinion of the investigator may interfere with 
study parameters; 


 
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2. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), 
or active ocular inflammation at Visit 1; 
3. Have worn contact lenses within 7 days of Visit 1 or anticipate using 
contact lenses during the study; 
4. Have used any eye drops within 2 hours of Visit 1; 
5. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery 
within the last 12 months; 
6. Have used cyclosporine 0.05% or lifitigrast 5.0% ophthalmic solution 
within 45 days of Visit 1; 
7. Have any planned ocular and/or lid surgeries over the study period or any 
ocular surgery within the last 6 months; 
8. Be using or anticipate using temporary punctal plugs during the study that 
have not been stable within 30 days of Visit 1; 
9. Be currently taking any topical ophthalmic prescription (including 
medications for glaucoma) or over-the-counter (OTC) solutions, artificial 
tears, gels or scrubs, and cannot discontinue these medications for the 
duration of the trial (excluding medications allowed for the conduct of the 
study); 
10. Have corrected visual acuity greater than or equal to logarithm of the 
minimum angle of resolution (logMAR) + 0.7 as assessed by Early 
Treatment of Diabetic Retinopathy Study (ETDRS) scale in both eyes at 
Visit 1; 
11. Be a woman who is pregnant, nursing, or planning a pregnancy; 
12. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 3 (or 
early termination visit) if of childbearing potential.  Non-childbearing 
potential is defined as a woman who is permanently sterilized (e.g., has 
had a hysterectomy or tubal ligation), or is post-menopausal (without 
menses for 12 consecutive months); 
13. Be a man or woman of childbearing potential who is not using an 
acceptable means of birth control; acceptable methods of contraception 
include: hormonal – oral, implantable, injectable, or transdermal 
contraceptives; mechanical – spermicide in conjunction with a barrier such 
as a diaphragm or condom; intrauterine device (IUD); or surgical 
sterilization of partner.  For non-sexually active males or females, 
abstinence may be regarded as an adequate method of birth control; 
however, if the subject becomes sexually active during the study, he/she 


 
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must agree to use adequate birth control as defined above for the 
remainder of the study; 
14. Have a known allergy and/or sensitivity to the test article or its 
components; 
15. Have a condition or be in a situation which the investigator feels may put 
the subject at significant risk, may confound the study results, or may 
interfere significantly with the subject’s participation in the study; 
16. Be currently enrolled in an investigational drug or device study or have 
used an investigational drug or device within 30 days of Visit 1; 
17. Have previously used ADX-102 ophthalmic solution; 
18. Be currently using any medication known to cause ocular drying that is 
not used on a stable dosing regimen for at least 30 days prior to Visit 1; 
19. Be unable or unwilling to follow instructions, including participation in all 
study assessments and visits. 
5.5 Withdrawal Criteria (if applicable) 
If at any time during the study the investigator determines that a subject’s safety has 
been compromised, the subject may be withdrawn from the study. 
Subjects may withdraw consent from the study at any time. 
Sponsor and/or investigator may discontinue any subject for non-compliance or any 
valid medical reason (see Section 8.6.2). 
6 STUDY PARAMETERS 
6.1 Efficacy Measures  
6.1.1 Exploratory Pharmacodynamic Variables 
The following exploratory endpoints will be tested: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Ora CalibraTM Ocular Discomfort Scale; 


 
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6.2 Safety Measures 
 Visual acuity (ETDRS); 
 Slit-lamp biomicroscopy; 
 Adverse event query; 
 Undilated Fundoscopy;  
 Intraocular Pressure; 
7 STUDY MATERIALS 
7.1 Study Drug(s) 
7.1.1 Formulations 
Randomized Study Treatments 
 ADX-102 Ophthalmic Solution (0.5%) 
 ADX-102 Ophthalmic Solution (0.1%) 
 ADX-102 Ophthalmic Lipid Solution (0.5%) 
7.1.2 Dispensation Schedule 
 At the end of Visit 1, qualified subjects will be randomized and the first 
dose of study drug will be administered in office. A supply of ADX-102 
Ophthalmic Solution (0.5%), ADX-102 Ophthalmic Solution (0.1%), or 
ADX-102 Ophthalmic Lipid Solution (0.5%) will be dispensed for 
dosing QID. 
 At the end of Visit 2, the unused vials from their Visit 1 kit will be re-
dispensed to subjects, and a second kit for dosing through Visit 3 will 
also be dispensed.  
 At Visits 2 and 3, remaining/used study drug will be collected from 
subjects for drug accountability.  
 Subjects will be instructed to not use study drug on the day of visits 
(Visit 2 and 3) prior to the visit. 
7.1.3 Instructions for Use 
Subjects will be instructed to dose in each eye QID (morning, noon, 
afternoon, and in the evening before bed). 
 
 
 
 


 
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7.2 Other Study Supplies 
Other study supplies include urine pregnancy tests, 
 
 
 
8 STUDY METHODS AND PROCEDURES 
8.1 Subject Entry Procedures 
8.1.1 Overview 
Subjects, as defined by the criteria in Sections 5.2, 5.3, and 5.4, will be 
considered for entry into this study. 
8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a 
subject’s medical treatment and/or prior to 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 (IRB). 
8.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the 
exclusion criteria (Section 5.4). 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria. 
8.1.5 Methods for Assignment to Treatment Groups 
Prior to initiation of study drug (at Visit 1), each subject who qualifies for 
entry will be assigned a screening number. All screening numbers will be 
assigned in strict numerical sequence at a site and no numbers will be 
skipped or omitted. If all inclusion and exclusion criteria are met at 
Visit 1, each qualifying subject will then be assigned a randomization 
number at the end of Visit 1.  
A randomization schedule will be provided to the investigational site. The 
randomization schedule will use block randomization, such that there will 
be an approximate equal number of subjects assigned to each of the three 
treatment arms at the site. The site staff will dispense to the patient the 
study kit labeled with the corresponding randomization number. The 
randomization number will be recorded on the patient’s source document 
and electronic case report form (eCRF). A new kit will be dispensed at 
Visit 2 based on the subject’s randomization. The Sponsor, Investigators, 


 
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and study staff will be masked during the randomization process and 
throughout the study.  
8.2 Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be 
recorded on the subject’s source document and corresponding eCRF along with the 
reason the medication was taken. 
Concurrent enrollment in another investigational drug or device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the 
Exclusion Criteria (Section 5.4).  
8.2.2 Escape Medications 
No escape medications are required for this study. 
8.2.3 Special Diet or Activities 
No special diets or activities are required for this study. 
8.3 Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
The following procedures will be performed (see Appendix 2 for 
description): 
Visit 1 (Day 1):  Screening & Enrollment 
 Informed consent / HIPAA; 
 Demographic data and medical / medication history; 
 Review of qualification criteria; 
 Urine pregnancy test (for females of childbearing potential); 
 Ora Calibra® Ocular Discomfort; 
 
 
 
 
 
 
 
 Visual Acuity (ETDRS); 
 Slit-lamp Biomicroscopy; 
 
 
 
 
 At least 20-minute wait; 
 
 


 
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 Fluorescein staining – Ora Calibra®;  
 Lissamine Green staining – Ora Calibra®; 
 
 
 
 
 Intraocular Pressure; 
 Undilated Fundoscopy; 
 Adverse event query; 
 Review of qualification criteria; 
 Randomization & Dispensation of study drug kit according to 
randomization for QID dosing until Visit 2; 
 
 
 
 
 Subjects will be instructed to dose in each eye four times daily 
(morning, noon, afternoon, and in the evening before bed); 
o Subjects will be instructed to dose in each eye before bed in the 
evening of Visit 2; 
o Subjects will be instructed to not dose with study drug on the 
morning of their next visit (Visit 2); 
 Qualified subjects will be scheduled for Visit 2. 
Visit 2 (Day 8 ± 1):  1-Week Follow-Up  
 Collection and review of study drug; 
 Subject will be asked if he/she dosed with study drug on the morning 
of the visit; if the subject indicates he/she dosed that morning, he/she 
should wait at least 4 hours from the time of dosing before efficacy 
assessments are performed; 
 Medical/medication history update; 
 Adverse event query; 
 Ora Calibra® Ocular Discomfort; 
 
 
 
 
 
 
 Visual Acuity (ETDRS); 
 Slit-lamp Biomicroscopy; 
 
 
 
  
 Dispensation of study drug kits for QID dosing until Visit 3; 
 
 
 
 


 
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 Subjects will be instructed to dose in each eye four times daily 
(morning, noon, afternoon, and in the evening before bed); 
o Subjects will be instructed to dose in each eye before bed the 
evening of Visit 3; 
o Subjects will be instructed to not dose with study drug on the 
morning of their next visit (Visit 3); 
 Subjects will be scheduled for Visit 3. 
Visit 3 (Day 29 ± 2): 4-Week Follow-Up and Study Exit 
 Collection and review of study drug; 
 Subject will be asked if he/she dosed with study drug on the morning 
of the visit; if the subject indicates he/she dosed that morning, he/she 
should wait at least 4 hours from the time of dosing before efficacy 
assessments are performed; 
 Medical/medication history update; 
 Adverse event query; 
 Urine pregnancy test (for females of childbearing potential); 
 Ora Calibra® Ocular Discomfort; 
 
 
 
 
 
 
 
 Visual Acuity (ETDRS); 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 Intraocular Pressure; 
 Undilated Fundoscopy; 
 Adverse event query; 
 Study Exit. 
Early Termination/Discontinuation  
If a subject is discontinued from the study prior to Visit 3 (Day 29 ± 2), 
then all safety evaluations that are to be performed at Visit 3 (Day 29 ± 2) 


 
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should be performed on the day of discontinuation (early termination) or 
at the discretion of the investigator.  
Adverse Events (both elicited and observed) and serious adverse events 
(SAEs) will be monitored throughout the study.  The investigator will 
promptly review all adverse events (both elicited and observed) for 
accuracy and completeness.  All adverse events will be documented on 
the appropriate source document and case report form. 
If a female reports a pregnancy or has a positive pregnancy test during the 
study the investigator will notify Ora immediately.  The investigator shall 
request from the subject and/or the subject’s physician copies of all related 
medical reports during the pregnancy and shall document the outcome of 
the pregnancy.  The investigator will retain these reports together with 
the subject’s source documents and will provide a copy of all 
documentation to Ora. The pregnant subjects will be discontinued from 
the study as per the exclusion criteria. 
8.4 Schedule of Visits, Measurements, and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All 
procedures performed at an unscheduled visit will be recorded in the 
source documents and on the Unscheduled Visit eCRF pages. Any 
procedure indicated in the eCRF that is not performed should be indicated 
as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
 Slit-lamp Biomicroscopy; 
 Visual Acuity; 
 Intraocular Pressure; 
 Urine Pregnancy Test; 
 Undilated Fundoscopy; 
 Assessment of Adverse Events; 
 Assessment of concurrent medications and/or treatments; and 
 Any other assessments needed in the judgment of the investigator. 
8.5 Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of study drug at the end 
of Visits 1 and 2, and given written instructions. The used and unused study drug 


 
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vials will be collected at each visit from Visit 2 up to and including Visit 3 to assess 
dosing and symptom assessment compliance. 
 
 
 
  
8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued at any time prior to their completion of the 
study due to: 
 adverse events; 
 unmasking when medically necessary; 
 protocol violations; 
 administrative reasons (e.g., inability to continue, lost to follow 
up); 
 sponsor termination of study; 
 subject choice (e.g., withdrawal of consent); and 
 other. 
Note: In addition, any subject may be discontinued for any sound medical 
reason at the discretion of the investigator. 
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. 
Discontinued subjects will not be replaced. 
8.7 Study Termination 
The study may be stopped at any time by the investigator, the Sponsor, and/or Ora 
with appropriate notification. 
8.8 Study Duration 
An individual subject’s participation will involve 3 visits over approximately a 
4-week period (28 days). 
8.9 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to 
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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, Inc. quality assurance 
and or its designees may carry out on-site inspections and/or audits, which may 
include source data checks.  Therefore, direct access to the original source data will 
be required for inspections and/or audits.  All inspections and audits will be carried 
out giving consideration to data protection as well as subject confidentiality to the 
extent that local, state, and federal laws apply. 
 
 


 
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9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related.  An 
adverse event can therefore be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease occurring after the subject started 
dosing with the study drug, without any judgment about causality.  Any pre-existing 
medical condition that worsens after administration of the study drug will also be 
considered a new adverse event.   
If there is a worsening of a medical condition that was present prior to the 
administration of the study drug, this should also be considered a new adverse event 
and reported.  Any medical condition present prior to the administration of the study 
drug that remains unchanged or improved should not be recorded as an adverse event 
at subsequent visits. 
Study drug includes the investigational drug under evaluation. 
Documentation regarding the adverse event should be made as to the nature, date of 
onset, end date, severity, relationship to study drug, action(s) taken, seriousness, and 
outcome of any sign or symptom observed by the physician or reported by the subject 
upon indirect questioning. 
9.1.1 Severity 
Severity of an adverse event is defined as a qualitative assessment of the 
degree of intensity of an adverse event as determined by the investigator 
or reported to him/her by the patient/subject.  The assessment of severity 
is made irrespective of relationship to study drug or seriousness of the 
event and should be evaluated according to the following scale: 
 
 
 
 
 
 
 
 
 
 
9.1.2 Relationship to Study Drug 
The relationship of each adverse event to the investigational product 
should be determined by the investigator (in a blinded manner) using 
these explanations: 


 
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 Definite: When there are good reason and sufficient 
documentation to demonstrate a direct causal relationship 
between investigational product and adverse event. 
 Probable: When there are good reasons and sufficient 
documentation to assume a causal relationship in the sense of 
plausible, conceivable, likely but not necessarily highly probable. 
 Possible: When there is sufficient information to accept the 
possibility of a causal relationship in the sense of not impossible 
and not unlikely, although the connection is uncertain or doubtful, 
for example; due to missing data or insufficient evidence. 
 None: When there is sufficient information to accept a lack of a 
causal relationship, in the sense of impossible and improbable. 
 Unclassified: When the causal relationship is not assessable for 
whatever reason due to insufficient evidence, conflicting data or 
poor documentation. 
9.1.3 Expectedness 
The expectedness of an adverse event should be determined based upon 
existing safety information about the study drug using these explanations: 
 Unexpected: An adverse event that is not listed in the 
Investigator’s brochure or is not listed at the specificity or severity 
that has been observed. 
 Expected: An adverse event that is listed in the Investigator’s 
brochure at the specificity and severity that has been observed. 
 Not Applicable: Any adverse event that is unrelated to the study 
drug. 
Adverse events that are mentioned in the Investigator’s brochure as 
occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an adverse 
event, but the final classification is subject to the Medical Monitor’s 
determination. 
9.2 Serious Adverse Events 
An adverse event is considered serious if, in the view of either the investigator or 
Sponsor, it results in any of the following outcomes: 
 Death; 
 A life-threatening adverse event; 
Note:  An adverse event is considered “life-threatening” if, in the view of 
either the investigator or Sponsor, its occurrence places the patient or subject 


 
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at immediate risk of death.  It does not include an adverse event 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 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 patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
9.3 Procedures for Reporting Adverse Events 
All adverse events and their outcomes must be reported to Ora, the study sponsor, and 
the institutional review board (IRB)/independent ethics committee (IEC) as required 
by the IRB/IEC, federal, state, or local regulations and governing health authorities 
and recorded on the appropriate eCRF. 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All adverse events that are ‘suspected’ and ‘unexpected’ are to be reported 
to Ora, the study sponsor and the IRB/IEC as required by the IRB/IEC, 
federal, state, or local regulations and governing health authorities. 


 
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9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all serious adverse events, regardless of 
relationship to the study drug, must be immediately reported.  All 
information relevant to the serious adverse event must be recorded on the 
appropriate case report forms.  The investigator is obligated to pursue 
and obtain information requested by Ora and/or the sponsor in addition to 
that information reported on the case report form.  All subjects 
experiencing a serious adverse event must be followed up and the outcome 
reported. 
In the event of a serious adverse event, the investigator must notify Ora 
and the Sponsor immediately; 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 Ora and the study sponsor with 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 study drug; and inform the IRB of the adverse 
event within their guidelines for reporting serious adverse events. 
Contact information for reporting Serious Adverse Events:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4 Procedures for Unmasking of Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a 
subject. When possible (i.e., in non-emergent situations), Ora and/or the study 
sponsor should be notified before unmasking study drug. The unmasked subject will 
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9.5 Type and Duration of the Follow-up of Subjects after Adverse 
Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the Investigator does not expect any further 
improvement or worsening of the AE. If the patient is lost to follow-up, the 
Investigator should make 3 reasonable attempts to contact the patient via telephone, 
post, or certified mail. All follow-up will be documented in the subject’s source 
document. Non-serious AEs identified on the last scheduled contact must be recorded 
on the AE eCRF with the status noted.  
If the investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated 
Report Form must be completed and faxed to Ora within 24 hours of the site’s 
awareness of the new information. The original SAE form is not to be altered. The 
report should describe whether the event has resolved or continues and how the event 
was treated. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
The following analysis populations will be considered: 

Intent-to-Treat Population – The intent-to-treat (ITT) population includes all
randomized subjects. Subjects in the ITT population will be analyzed as
randomized.

Per-Protocol Population – The per-protocol (PP) population includes subjects
in the ITT population who do not have significant protocol deviations and
who complete the study. Protocol deviations will be assessed prior to database
lock and unmasking. Subjects in the PP population will be analyzed as treated.

Safety Population – The safety population includes all randomized subjects
who have received at least one dose of the investigational product. Subjects in
the Safety population will be analyzed as treated.
 
 
 
10.2 
Statistical Hypotheses 
This is a Phase 2a study to assess the safety, tolerability and pharmacodynamic 
activity of ADX-102 Ophthalmic Solution in subjects with dry eye syndrome. 
There are no primary endpoints and no formal statistical hypotheses. 


 
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10.3  Sample Size 
 
 
 
 
 
10.4 Statistical Analysis 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
10.4.2 Unit of Analysis 
 
 
  
 
 
 
 
 
 
 
 
 


 
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10.4.3 Missing Data 
 
 
 
 
 
10.4.4 Multiplicity Consideration 
 
 
 
10.4.5 Primary Efficacy Analyses 
There are no primary endpoints in this Phase 2a study. 
10.4.6 Secondary Efficacy Analyses 
There are no secondary endpoints in this Phase 2a study. 
10.4.7 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. Frequencies 
and percentages of subjects with treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs causing premature discontinuation 
will be provided by treatment group. An AE is treatment emergent if it 
occurs or worsens after the first dose of study treatment. Furthermore, 
frequencies will be given of subjects with TEAEs by system organ class; 
by system organ class and preferred term; by system organ class, preferred 
term and maximal severity; by system organ class and preferred term for 
treatment-related TEAEs; and by system organ class, preferred term, and 
study day of onset. Separate summaries will be performed for ocular and 
non-ocular AEs.  
 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, 
undilated fundoscopy, and intraocular pressure will be summarized by 
treatment group and visit using descriptive statistics. Changes or shifts 
from baseline will also be summarized where appropriate. For assessments 
performed by eye, study eye, and fellow eye will be summarized 
separately.  
10.4.8 Exploratory Pharmacodynamic (Efficacy) Measures 
 
 
 
 
  


 
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10.4.9 Interim Analyses 
 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs), including the International Council 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 study drugs in the countries involved 
will be adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific 
procedures are initiated.  Signed and dated written informed consent 
must be obtained from each subject and/or from the subject’s parent or 
legal guardian prior to enrollment into the study.  If the subject is under 
the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent 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. 
If informed consent is taken under special circumstances (oral informed 
consent), then the procedures to be followed must be determined by Ora 
and/or study Sponsor and provided in writing by Ora and/or study Sponsor 
prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with Institutional Review 
Board regulations (U.S. 21 CFR Part 56.103).  The investigator must 


 
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obtain appropriate IRB approval before initiating the study and 
re-approval at least annually. 
Only an IRB/ERC approved version of the informed consent form will be 
used. 
11.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
11.3 Subject Confidentiality 
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 (FDA), the 
Department of Health and Human Services (DHHS), 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 study drug may ultimately be marketed, but 
the subject’s identity will not be disclosed in these documents. 
11.4 Documentation 
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 electrocardiographs (EKGs).  The investigator’s 
copy of the case report forms serves as the investigator’s record of a subject’s study-
related data. 
11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of 
the distribution and use of all study drug and copies of case report forms 
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 study drug. These documents will be retained for a 
longer period if required by the applicable regulatory requirements or by 


 
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an agreement with the sponsor.  It is the responsibility of the Sponsor to 
inform the investigator/institution as to when these documents no longer 
need to be retained. 
If the responsible investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping study records, custody must 
be transferred to a person who will accept the responsibility.  The 
Sponsor must be notified in writing of the name and address of the new 
custodian. 
11.5 Labeling, Packaging, Storage, Accountability, and Return or 
Disposal of Study Drug 
11.5.1 Labeling/Packaging 
  
 
 
11.5.2 Storage of Study Drug 
 
 
 
  
11.5.3 Accountability of Study Drug 
 
 
 
  
 
 
 
 
 
  
11.5.4 Return or Disposal of Study Drug 
 
11.6 Recording of Data on Source Documents and Electronic Case 
Reports Forms (eCRFs) 
All subject data will be captured in the subject source documents which will be 
transcribed in the eCRFs. The investigator is responsible for ensuring that study data 
is completely and accurately recorded on each subject’s eCRF, source documents, 
and all study-related materials. All study data should also be attributable, legible, 
contemporaneous, and original. Recorded datum should only be corrected in a 


 
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manner that does not obliterate, destroy, or render illegible the previous entry (e.g., by 
drawing a single line through the incorrect entry and writing the revision next to the 
corrected data). An individual who has corrected a data entry should make clear who 
made the correction and when, by adding to the correction his/her initials as well as 
the date of the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 
21 CFR Part 11 requirements, and will be performed only by staff who have been 
trained on the system and have access to the system. Data will not be entered for 
screen failure subjects. An audit trail will be maintained within the electronic system 
to capture all changes made within the eCRF database. After the end of the study and 
database lock, compact discs (CDs) containing copies of all applicable subjects’ 
eCRFs will be provided to each Investigator Site to be maintained on file by the 
Investigator. 
11.7 Handling of Biological Specimens 
 
 
   
11.8 Publications 
 
  
 
 
 
 
 


 
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12 REFERENCES 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 


 
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Appendix 2:  Examination Procedures, Tests, Equipment, and 
Techniques 


 
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Visual Acuity Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Ora Calibra® Ocular Discomfort Scale  
 
   
 
 
 
 
 
 
 


 
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Appendix 3:  Amendment Summary of Changes  
Not applicable 
 
 
 
 
 
 
 
 
 
 
 


 
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SAP_003.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
A Single-Center, Phase 2a, Randomized, Double-Masked, Clinical 
Study to Assess the Safety, Tolerability, and Pharmacodynamic 
Activity of ADX-102 Ophthalmic Solution in Subjects with Dry Eye 
Syndrome 
 
 
Sponsor:   
 
Aldeyra Therapeutics, Inc. 
 
 
 
 
 
 
Protocol Number: 
ADX-102-DES-007 
 
 
   
 
 
 
 
 
 
 
 
Date:    
 
02-JUN-2017 
Version:  
 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 




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


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13. 
Efficacy Analyses ................................................................................................................... 15 
13.1 Primary Analysis .................................................................................................................... 15 
13.2 Secondary Analyses .............................................................................................................. 16 
14. 
Exploratory Analyses ............................................................................................................. 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. 
Safety Analyses ..................................................................................................................... 22 
15.1 Adverse Events ...................................................................................................................... 22 
15.2 Visual Acuity (ETDRS) ........................................................................................................... 24 
15.3 Slit-Lamp Biomicroscopy Examination .................................................................................. 24 
15.4 Undilated Fundoscopy Examination ...................................................................................... 24 
15.5 Intraocular Pressure (IOP) ..................................................................................................... 25 
16. 
Interim Analyses .................................................................................................................... 25 
17. 
Changes from Protocol-Stated Analyses ............................................................................... 25 
18. 
Revision History ..................................................................................................................... 25 
19. 
Tables .................................................................................................................................... 25 
20. 
Listings ................................................................................................................................... 30 
21. 
Figures ................................................................................................................................... 31 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCVA 
Best Corrected Visual Acuity 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
OSDI 
Ocular Surface Disease Index 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAAS 
Software-as-a-Service 
SAE 
Serious Adverse Event 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TE-SAE 
Serious Treatment-Emergent Adverse Event 
VA 
Visual Acuity 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol ADX-102-DES-007, version 1.0 dated 27MAR2017. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The objective of this study is to evaluate the safety, tolerability and pharmacodynamic activity of ADX-
102 Ophthalmic Solutions (0.5% and 0.1%) and ADX-102 Ophthalmic Lipid Solution (0.5%) in subjects 
with dry eye syndrome. 
2.1 Study Variables 
In this Phase 2a study there are no primary or secondary endpoints.  Exploratory pharmacodynamic 
variables and safety variables follow. 
2.2 Exploratory Pharmacodynamic Variables 
The exploratory pharmacodynamic variables include the following: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Ora Calibra® Ocular Discomfort Scale; 
• 
 
 
 
 
 






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4. Study Treatments 
4.1 Method of Assigning Subjects to Treatment Groups 
Prior to initiation of study drug (at Visit 1), each subject who qualifies for entry will be assigned a 
screening number. All screening numbers will be assigned in strict numerical sequence at a site and no 
numbers will be skipped or omitted. If all inclusion and exclusion criteria are met at Visit 1, each 
qualifying subject will then be assigned a randomization number at the end of Visit 1.  
A randomization schedule will be provided to the investigational site. The randomization schedule will 
use block randomization, such that there will be an approximate equal number of subjects assigned to 
each of the three treatment arms at the site. The site staff will dispense to the subject the study kit based 
on the subject’s randomization number. The randomization number will be recorded on the subject’s 
source document and electronic case report form (eCRF). A new kit will be dispensed at Visit 2 based 
on the subject’s randomization. The Sponsor, Investigators, and study staff will be masked during the 
randomization process and throughout the study.   
4.2 Masking and Unmasking 
All subjects, investigators, and study personnel involved with the conduct of the study will be masked 
with regard to treatment assignments. When medically necessary, the investigator may need to 
determine what treatment arm has been assigned to a subject. When possible (i.e., in non-emergent 
situations), Ora and/or the study sponsor should be notified before unmasking study drug. The 
unmasked subject will be discontinued from the study.  
5. Sample Size and Power Considerations 
 
 
 
 
 
6. Data Preparation 
Electronic Case Report Forms (eCRF) will be developed by Statistics and Data Corporation, 
Incorporated (SDC) following SDTM standards unless otherwise specified by Aldeyra.  Data from source 
documents will be entered into the eCRF by site personnel.  All users will complete role-based system 
and study-specific eCRF training prior to receiving access to the study database. User access will be 
granted based on a user’s role in the study and will be controlled through individual login credentials 
including a unique User ID and password. 


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After data are entered into the clinical study database, electronic edit checks and data review will be 
performed.  All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document.  When the database has been declared to be complete and accurate, the 
database will be locked.  Any changes to the database after data have been locked can only be made 
with the approval of Aldeyra and Ora in consultation with SDC.  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
All data management requirements are met according to SDC standard operating procedures 
(SOP), including data entry, performance of edit and validation checks, documentation and 
resolution of data queries, and database lock with written authorization provided by appropriate 
SDC, Aldeyra and Ora personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined; and 
• 
Randomized treatment codes have been unmasked. 
7. Analysis Populations 
Analysis populations include the intent-to-treat (ITT) population, the per-protocol (PP) population, and 
the Safety population.  The statistical analysis of safety data will be performed on the Safety population. 
The analysis of baseline and exploratory efficacy data will be performed on the ITT population, and may 
be performed on the PP population as sensitivity analyses if it differs substantially from the ITT 
population. 
7.1 Intent-to-Treat 
The ITT population includes all randomized subjects. Subjects in the ITT population will be analyzed as 
randomized.  
7.2 Per Protocol 
The PP population includes subjects in the ITT population who do not have significant protocol 
deviations and who complete the study. Protocol deviations will be assessed prior to database lock and 
unmasking. Subjects in the PP population will be analyzed as treated.  


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7.3 Safety 
The Safety population includes all randomized subjects who have received at least one dose of the 
investigational product. Subjects in the Safety population will be analyzed as treated.  
8. General Statistical Considerations 
8.1 Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of analysis will be the 
study eye, or the “worst eye,” as defined by the following:  
Worst Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria. In the case that both 
eyes are eligible for analysis, the worst eye will be the eye with worst (higher) total corneal fluorescein 
staining, based on the sum of the inferior, superior, and central regions, at Visit 1. If the total corneal 
staining is the same in both eyes then the eye with the worst (higher) Ora Calibra® Ocular Discomfort 
Scale score at Visit 1 will be the worst eye. If the total corneal staining and ocular discomfort scores are 
the same for both eyes, then the right eye will be selected as the worst eye. 
8.2 Missing or Inconclusive Data Handling 
 
 
   
8.3 Definition of Baseline 
 
 
8.4 Data Analysis Conventions 
 
 
 
 
 
 
 
 
 
 
 


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Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum.  Minima and maxima will be reported 
with the same precision as the raw values; means and medians will be presented to one additional 
decimal place than reported in the raw values.  Standard deviations will be presented to two additional 
decimal places than reported in the raw values.  Summaries for discrete variables will include frequency 
counts and percentages.  All percentages will be rounded to one decimal place (i.e., XX.X%).     
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified.  
Confidence intervals (CI) for differences between treatment groups will be two-sided at 80% and 95% 
confidence levels where appropriate.  All p-values will be rounded to four decimal places; p-values less 
than 0.0001 will be presented as “<0.0001”; p-values greater than 0.9999 will be presented as “>0.9999”. 
8.5 Adjustments for Multiplicity 
 
 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study.  Subjects who are not discontinued 
from the study will be considered study completers.  Disposition will be summarized by treatment group 
and for all subjects. 
The number of subjects in each of the analysis populations (ITT, PP and Safety) will be displayed by 
treatment and percentages will be calculated using randomized subjects as the denominator. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment group for all randomized subjects.  The reasons 
for study discontinuation that will be summarized include: (AE, protocol violation, administrative reasons 
(e.g., inability to continue, lost to follow up), sponsor termination of study, subject choice, and other.  A 
subject listing will be provided that includes the date of and reason for premature study discontinuation. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
group for all randomized subjects.  The protocol deviations that will be summarized include:  Informed 
Consent, Inclusion / Exclusion and Randomization, Test Article / Study Drug Instillation and Assignment 
at Site, Improper Protocol Procedures at Site, Site’s Failure to Report SAE / AE, Visit Out of Window, 
Subject’s Non-compliance with Test Article, Subject’s Use of Prohibited Concomitant Medication, 
Subject’s Failure to Follow Instructions, and Other.   A subject listing will be provided that includes the 
date and description of each deviation. 


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In addition, subject listings will be provided that include treatment, whether inclusion and exclusion 
criteria were met, and inclusion in the ITT, Safety, and PP populations. 
10. Demographic and Pretreatment Variables 
10.1 Demographic Variables 
The demographic variables collected in this study include age, sex, race, ethnicity and iris color.  
Demographic variables will be summarized, overall and by treatment group, for the ITT and Safety 
populations, separately. 
Age (years) will be summarized using continuous descriptive statistics.  Age will also be categorized as 
follows:  <65 years and ≥65 years.  Age will be reported in years and calculated using the following 
formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
The number and percentage of subjects will be presented for age category, sex, race, ethnicity and iris 
color.   
A subject listing that includes all demographic variables for the ITT population will be provided. 
10.2 Pretreatment Variables 
Baseline disease characteristics will be summarized by treatment group using continuous descriptive 
statistics for Ora Calibra® Ocular Discomfort Scale, corneal sum and total fluorescein staining, 
conjunctival sum and total lissamine green staining, TFBUT, SANDE questionnaire, VA, tear osmolarity, 
unanesthetized Schirmer’s test, OSDI©, and IOP. 
11. Medical History and Concomitant Medications 
11.1 Medical History 
Medical history will be coded using MedDRA Version 20.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment group at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) 
using the ITT population.  Ocular medical history will be similarly summarized at the subject and event 
level.  If a subject reports the same PT multiple times within the same SOC, that PT will only be reported 
once within that SOC.  As with the PT, if a subject reports multiple conditions within the same SOC, that 
SOC will only be reported once.   
Listings of medical history will be generated separately for ocular and non-ocular data. 


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11.2 Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary March 2017 and summarized to the 
therapeutic drug class (Anatomical Therapeutic Chemical (ATC) 4 classification) and preferred name.  
ATC classifications are applied based on the route and indication by which the drug was taken. If no 
route or indication is reported/available, the first ATC in alphabetic order will be applied.   In cases where 
the trade name of the drug is reported, SDC will code to the trade name.  If this is not available in the 
dictionary, then the generic name of the drug will be selected. If neither the trade nor generic names are 
available, SDC will code the medication to the appropriate general category based on the indication and 
route.  If a multi-ingredient/combination drug trade name is not available in the current dictionary, SDC 
will code to the generic combination if available.  If this is not available, SDC will code to the General 
category based on the reported Indication.  Additional coding guidelines are specified in the Data 
Management Plan (DMP).  Terms that remain uncoded after the coding guidelines have been followed 
will be forwarded to the Medical Monitor along with a list of potential coding links available in the 
dictionary.  The Medical Monitor will either select one of the terms from the potential coding links or 
specify an alternate term that is available in the dictionary. 
Concomitant medications are defined as those medications listed as having been taken 1) within 30 
days prior to initiation of study drug administration and continuing for any period of time following the 
first administration of study drug or 2) at any time following the first administration of study drug. 
Concomitant medications will be summarized using the ITT population.  Ocular and non-ocular 
medications will be summarized separately.  Medications will be tabulated for each treatment group 
using frequencies and percentages.  Subjects may have more than 1 medication per ATC text.  At each 
level of subject summarization, a subject will be counted once if he/she reports 1 or more medications.  
Percentages will be based on the number of subjects in each treatment group.  Listings of concomitant 
medications will be generated separately for ocular and non-ocular data. 
12. Dosing Compliance and Treatment Exposure 
12.1 Dosing Compliance 
 
 
 
 
 
  


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12.2 Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following: 
Extent of Exposure (days) = Date of completion/discontinuation – date of Visit 1 (Day 1) 
Extent of treatment exposure for subjects who were lost to follow-up will be calculated in days using the 
following: 
Extent of Exposure (days) = Date of last recorded visit – date of Visit 1 (Day 1) + 1 
Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group, using the Safety population.  A subject listing 
of treatment exposure will also be produced. 
13. Efficacy Analyses 
13.1 Primary Analysis 
There are no primary endpoints in this Phase 2a study. 


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13.2 Secondary Analyses 
There are no secondary endpoints in this Phase 2a study. 
14. Exploratory Analyses 
 
 
 
 
The following exploratory endpoints will be tested: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Ora Calibra® Ocular Discomfort Scale; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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.   


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14.6 Ora Calibra® Ocular Discomfort Scale 
Ocular discomfort scores will be subjectively graded by the subjects using the Ora Calibra® Ocular 
Discomfort Scale at all scheduled visits. The ocular discomfort scale ranges from 0 to 4 where 
 
 
   
Continuous descriptive statistics, including 80% and 95% CIs, as well as changes from baseline will be 
summarized by treatment group and visit.  Pairwise two-sample t-tests will be employed to compare the 
observed treatment means as well as the changes from baseline at each visit.  The mean treatment 
differences, two-sided 80% and 95% confidence intervals (CIs) for the mean differences and p-values 
will be reported.  Wilcoxon rank sum tests will be conducted as sensitivity analyses to assess robustness 
of the results.  Changes from baseline will also be compared between treatment groups using an 
ANCOVA model that includes the baseline score as a covariate as an additional sensitivity analysis.  All 
analyses will be performed on the ITT population with LOCF. 
Ocular discomfort changes from baseline in the study eye will be displayed graphically in a bar chart 
with standard error bars by visit and treatment group. 
 
 
 
 
 
 
 
 
 


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15. Safety Analyses 
All safety analyses will be conducted using the Safety population. 
15.1 Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not the event is considered drug-related.  An AE can therefore be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease occurring after the subject 
started dosing with the study drug, without any judgment about causality.  Any pre-existing medical 
condition that worsens after administration of the study drug will also be considered a new adverse 
event.  The AE reporting period ends upon study exit.  Study drug includes the investigational drug 
under evaluation.  All AEs will be coded using MedDRA Version 20.0.   
Treatment-emergent adverse events (TEAEs) are defined as any adverse event that occurs or worsens 
after the first dose of study treatment.  AEs recorded in the eCRF which began prior to treatment will not 
be included in the summary tables but will be included in the AE data listings. 
An overall summary will be presented that includes the number of AEs, TEAEs, serious AEs (SAE), and 
serious TEAEs (TE-SAE).  The summary will also include the number and percentage of subjects 
withdrawn due to an AE, the number and percentage of subjects with an AE resulting in death, and the 
number and percentage of subjects who experienced at least one AE, TEAE, SAE and TE-SAE, by 
treatment group and for all subjects.  This summary will include breakdowns of AEs further categorized 
as ocular or non-ocular. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE.  These summaries will be presented by SOC and PT.  Non-ocular 
TEAEs will be summarized using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT.  Ocular TEAEs will be similarly summarized at the subject and 
event level as well as for study and fellow eyes separately.  If a subject reports the same PT multiple 
times within the same SOC, that PT will only be reported once within that SOC.  As with the PT, if a 
subject reports multiple conditions within the same SOC, that SOC will only be reported once.  In the 
summary, SOC will be listed in order of descending frequency for all subjects; PTs will be listed in order 
of descending frequency for all subjects within each SOC.  The occurrence of non-ocular and ocular 
TEAEs will also be tabulated by SOC, PT, and maximal severity. 
Separate summaries will be provided for the following categories of AEs:  
• 
Ocular TEAEs in the study eye 
• 
Ocular TEAEs in the fellow eye 
• 
Non-ocular TEAEs  


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• 
Treatment-related ocular TEAEs 
• 
Treatment-related non-ocular TEAEs 
• 
SAEs 
Severity of an adverse event is defined as a qualitative assessment of the degree of intensity of an 
adverse event as determined by the investigator or reported to him/her by the patient/subject.  The 
assessment of severity is made irrespective of relationship to study drug or seriousness of the event 
and should be evaluated according to the following scale: 
 
 
 
 
 
 
 
 
 
Summaries of TEAEs by maximal severity will be presented for ocular AEs and non-ocular AEs 
separately.  The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC 
and PT within each SOC by treatment group.  To count the number of subjects with any TEAEs, if a 
subject has multiple TEAEs coded to the same PT within the same SOC, the subject will be counted 
once under the maximal severity. 
The relationship of each adverse event to the investigational product should be determined by the 
investigator (in a blinded manner) using these explanations: 
• 
Definite: When there are good reason and sufficient documentation to demonstrate a direct 
causal relationship between investigational product and adverse event. 
• 
Probable: When there are good reasons and sufficient documentation to assume a causal 
relationship in the sense of plausible, conceivable, likely but not necessarily highly probable. 
• 
Possible: When there is sufficient information to accept the possibility of a causal relationship 
in the sense of not impossible and not unlikely, although the connection is uncertain or 
doubtful, for example; due to missing data or insufficient evidence. 
• 
None: When there is sufficient information to accept a lack of a causal relationship, in the 
sense of impossible and improbable. 
• 
Unclassified: When the causal relationship is not assessable for whatever reason due to 
insufficient evidence, conflicting data or poor documentation. 
Only probable and definite TEAEs are considered as treatment-related TEAEs.  


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All AEs will be presented in a subject listing that classifies each AE as ocular or non-ocular and indicates 
whether it is a TEAE.  Separate listings will be produced for AEs leading to study discontinuation,  AEs 
leading to death and SAEs. 
15.2 Visual Acuity (ETDRS) 
The visual acuity procedure will be performed according to Ora, Inc. standard operating procedures 
and/or guidance documents.  The logarithm of the minimum angle of resolution (logMAR) VA must be 
assessed using an ETDRS chart. The procedure used will be consistent with the recommendations 
provided for using the ETDRS eye chart. Visual Acuity should be evaluated at the beginning of each 
visit in the study (i.e., prior to slit-lamp examination). Subjects should use their most recent correction to 
attain their best-corrected visual acuity (BCVA). 
The observed and change from baseline visual acuity will be summarized for each eye (study eye and 
fellow eye) using continuous descriptive statistics by visit for each treatment group.  A subject listing of 
visual acuity will also be produced.   
15.3 Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, iris, lens, and lid 
will be performed at each visit, and potentially at an Early Termination Visit.  The results will be graded 
as normal, Abnormal Not Clinically Significant (NCS) or Abnormal Clinically Significant (CS).  Abnormal 
findings will be described. 
The results will be summarized using counts and percentages for each treatment group at each visit for 
each eye (study eye and fellow eye).  Percentages will be based on the number of subjects in each 
treatment group with responses.  Shift tables for the slit-lamp biomicroscopy parameters will also be 
provided comparing each follow-up visit to baseline (Visit 1).  A subject listing of the slit-lamp 
biomicroscopy parameters will also be produced. 
15.4 Undilated Fundoscopy Examination 
An undilated fundoscopy exam will be performed during the study at Visits 1 and 3, and potentially at 
an Early Termination Visit.  Observations will be graded as Normal or Abnormal NCS or Abnormal CS.  
Abnormal findings will be described. The following will be examined: 
• 
Vitreous 
• 
Retina 
• 
Macula 
• 
Choroid 
• 
Optic Nerve