Clinical trial NCT05102409
Conditions: Dry Eye
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2021-09-09; Completion date: 2021-10-25
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
An Exploratory, Single-Center, Double-Masked, Crossover Clinical Trial to Assess Safety and Tolerability of 0.25% Reproxalap Ophthalmic Solution Compared to Xiidra® in Subjects with Dry Eye Disease in a Dry Eye Chamber

Detailed description:

Arms: arm 1: Single dose arm 2: Single dose
Interventions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) intervention 2: Xiidra® (5% lifitegrast ophthalmic solution)
Intervention descriptions: intervention 1: Reproxalap Ophthalmic Solution (0.25%) dosed once intervention 2: Xiidra® (5% lifitegrast ophthalmic solution) dosed once

Protocol documents:
Prot_SAP_001.pdf: 
CONFIDENTIAL 
This protocol is the confidential and proprietary information of 
 doing business as 
. It 
was developed  by 
 and should not be disclosed to a third party, with the exception of regulatory agencies and 
study audit personnel. 
 
 
An Exploratory, Single-Center, Double-Masked, Crossover Clinical Trial to Assess 
Safety and Tolerability of 0.25% Reproxalap Ophthalmic Solution Compared to Xiidra® 
in Subjects with Dry Eye Disease in a Dry Eye Chamber 
Study Sponsor 
(Principal 
Investigator) 
 
  
  
 
  
  
 
Study Number(s) 
C1D01056 
Study Product(s) 
Product A: 0.25% Reproxalap Ophthalmic Solution (reproxalap) (Manufactured 
by Aldeyra Therapeutics, Inc.) 
Product B: Xiidra® (5% lifitegrast ophthalmic solution) (
 
) 
Clinical Research 
Organization 
 
 
 
 
Indication 
Dry Eye Disease (DED) 
Clinical Trial Phase 
Phase 2 
Regulatory Agency 
Health Canada 
Protocol Version 
Final 1.0 
Protocol Date 
29 Jun 2021 


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PROTOCOL VERSION CONTROL  
 
Version Number 
Notes/Summary of Changes 
Date 
Final 1.0 
Protocol Created 
29 Jun 2021 
 
 
 
 
 
 
 
 
 
 




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STUDY SPONSOR (PRINCIPAL INVESTIGATOR) APPROVAL SIGNATURE PAGE 
 
Study Title: An Exploratory, Single-Center, Double-Masked, Crossover Clinical Trial to Assess 
Safety and Tolerability of 0.25% Reproxalap Ophthalmic Solution Compared to Xiidra® in 
Subjects with Dry Eye Disease in a Dry Eye Chamber 
 
I agree to conduct this clinical trial as outlined in the approved protocol and accordance with all 
applicable federal government codes, acts and regulations, the ethical principles that have their 
origins in the Declaration of Helsinki and all amendments, Good Clinical Practice (GCP) 
requirements, the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidance E6 (R2), and Tri-Council Policy Statement 
(Canada) and to allow applicable regulatory agencies the opportunity to inspect study facilities 
and pertinent records at reasonable times and in a reasonable manner that ensures subject 
confidentiality. 
 
Principal Investigator 
  
  
  
 
  
  
 
 
 
Signature ______________________________________ Date __________________ 
 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ................................................................................................... 7 
2. 
SPONSOR REPRESENTATIVE (PRINCIPAL INVESTIGATOR) ........................................ 8 
3. 
STUDY ADMINISTRATIVE STRUCTURE ............................................................................ 8 
 
Clinical Research Organization ...................................................................................... 8 
 
Clinical Facilities ............................................................................................................. 8 
 
Central Institutional Review Board (IRB) ........................................................................ 8 
 
Safety Management ........................................................................................................ 8 
4. 
STUDY SUMMARY ................................................................................................................ 9 
5. 
STUDY SCHEMATIC ........................................................................................................... 13 
 
Endpoints ...................................................................................................................... 15 
5.1.1 
Exploratory Endpoints ........................................................................................... 15 
5.1.2 
Safety Endpoints ................................................................................................... 15 
6. 
INTRODUCTION .................................................................................................................. 15 
 
Background and Study Rationale ................................................................................. 15 
 
Nonclinical Data ............................................................................................................ 16 
 
Effects in Humans ......................................................................................................... 16 
 
Benefit/Risk Assessment .............................................................................................. 17 
 
Rationale for Dose Selection ........................................................................................ 17 
7. 
OBJECTIVES AND ENDPOINTS ........................................................................................ 17 
 
Objectives ..................................................................................................................... 17 
8. 
STUDY DESIGN ................................................................................................................... 17 
 
Overall Study Design .................................................................................................... 17 
9. 
SUBJECT SELECTION ....................................................................................................... 18 
 
Number of Subjects ...................................................................................................... 18 
 
Inclusion Criteria for Study Volunteers ......................................................................... 18 
 
Exclusion and Restriction Criteria for Study Volunteers .............................................. 18 
9.3.1 
Exclusion Criteria .................................................................................................. 18 
9.3.2 
Restrictions and Concomitant Medications .......................................................... 20 
9.3.3 
Female Subjects of Childbearing Potential .......................................................... 21 
9.3.4 
Male Subjects........................................................................................................ 21 
10. STUDY PRODUCT AND TREATMENT SEQUENCE ......................................................... 22 


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Study Product and Treatment ....................................................................................... 22 
 
Treatment Sequence .................................................................................................... 22 
 
Masking and Unmasking .............................................................................................. 22 
10.3.1 
Masking ................................................................................................................. 22 
10.3.2 
Emergency Unmasking ......................................................................................... 22 
11. STUDY VISITS ..................................................................................................................... 23 
 
COVID-19 Screening .................................................................................................... 23 
 
Visit 1: Screening (Day -21 to -8) ................................................................................. 23 
 
Visits 2 (Day 1 + 2) and 3 (Day 8 + 2): Treatment/Dry Eye Chamber ......................... 24 
 
Phone call follow-up ...................................................................................................... 24 
12. STUDY ASSESSMENTS AND PROCEDURES.................................................................. 24 
 
Efficacy Assessments ................................................................................................... 24 
12.1.1 
Ocular Discomfort Score and Ocular Itching Score ............................................. 24 
 
Safety Assessments ..................................................................................................... 25 
12.2.1 
Snellen Visual Acuity (SVA).................................................................................. 25 
12.2.2 
Slit-lamp Exam (SLE) ........................................................................................... 25 
12.2.3 
Intraocular Pressure (IOP) .................................................................................... 25 
12.2.4 
Dilated Fundoscopy .............................................................................................. 25 
12.2.5 
COVID-19 Test (SARS-CoV-2) ............................................................................ 25 
12.2.6 
Demographics and Medical/Medication and Ocular History ................................ 25 
12.2.7 
Adverse Event Query/Concomitant Medication Query ........................................ 25 
13. ANALYSES AND REPORTS ............................................................................................... 26 
 
Final Integrated Report ................................................................................................. 26 
14. STATISTICAL CONSIDERATIONS .................................................................................... 26 
 
Statistical Analyses ....................................................................................................... 26 
 
Safety Analysis ............................................................................................................. 26 
 
Interim Analyses ........................................................................................................... 26 
 
Sub-group Analyses...................................................................................................... 26 
15. ADMINISTRATIVE STUDY RECORDS............................................................................... 26 
 
Subject Enrollment and Identification ........................................................................... 26 
 
Study Charts/Records and Source Documents ........................................................... 27 
 
Retention and Availability of Investigational Records .................................................. 28 
16. DRUG ACCOUNTABILITY .................................................................................................. 28 


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Product Shipment ......................................................................................................... 28 
 
Product Receipt ............................................................................................................ 28 
 
Product Storage ............................................................................................................ 28 
 
Drug Dose Package Labeling ....................................................................................... 28 
17. SUBJECT SAFETY MONITORING AND ADVERSE EVENTS .......................................... 28 
 
Subject Safety Monitoring ............................................................................................. 28 
17.1.1 
Pregnancy ............................................................................................................. 29 
 
Adverse Events ............................................................................................................. 29 
17.2.1 
Recording Adverse Events ................................................................................... 30 
17.2.2 
Reporting Serious Adverse Events ...................................................................... 31 
17.2.3 
Removal of Subjects from Study .......................................................................... 32 
17.2.4 
Termination of Study Due to Adverse Events ...................................................... 33 
18. ETHICS OF CONDUCT ........................................................................................................ 33 
19. QUALITY CONTROL AND QUALITY ASSURANCE ......................................................... 33 
 
Pandemic COVID-19 Response Plan .......................................................................... 34 
20. REGULATORY ..................................................................................................................... 35 
 
Institutional Review Board/ Health Canada .................................................................. 35 
 
Consent Document ....................................................................................................... 35 
 
Confidentiality................................................................................................................ 36 
 
Investigator's Statement ............................................................................................... 37 
21. REFERENCES ..................................................................................................................... 39 
 


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1. 
LIST OF ABBREVIATIONS 
TERM 
DEFINITION  
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
DEC 
Dry eye Chamber 
DED 
Dry Eye Disease 
DMP 
Data Management Plan 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
 
 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LASIK 
Laser-assisted in situ keratomileusis 
MedDRA 
Medical Dictionary for Regulatory Activities 
ºC 
Degrees Celsius 
PI 
Principal Investigator 
QA 
Quality Assurance 
RASP 
Reactive Aldehyde Species 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SLE 
Slit-lamp examination 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unsuspected Serious Adverse Reaction 
SVA 
Snellen Visual Acuity 
USA 
United States of America 
WOCBP 
Women of Childbearing Potential 
 


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2. 
SPONSOR REPRESENTATIVE (PRINCIPAL INVESTIGATOR) 
 
  
  
  
 
  
  
 
3. 
STUDY ADMINISTRATIVE STRUCTURE 
 
Clinical Research Organization 
 
 
 
 
 
Clinical Facilities 
 
 
 
 
 
 
 
 
 
 
Central Institutional Review Board (IRB) 
 
 
  
  
 
 
Safety Management  
 
 
 
 
 
 


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4. 
STUDY SUMMARY 
Study Title 
 
An Exploratory, Single-Center, Double-Masked, Crossover Clinical Trial to Assess 
Safety and Tolerability of 0.25% Reproxalap Ophthalmic Solution Compared to Xiidra® 
in Subjects with Dry Eye Disease in a Dry Eye Chamber 
Protocol Number 
C1D01056 
Study Phase 
Phase 2 
Study Objectives 
To explore the safety and tolerability of reproxalap compared to Xiidra® in a dry eye 
chamber. 
Study Endpoints 
Exploratory Endpoints:  
• 
Change in ocular discomfort score (0-10) from baseline over 45 minutes in the 
dry eye chamber 
• 
Change in ocular itching score (0-10) from baseline over 45 minutes in the dry 
eye chamber 
Safety Endpoints: 
• 
Snellen visual acuity (SVA) 
• 
Slit-lamp examination (SLE) 
• 
Adverse event (AE) query 
Study Design 
 
C1D01056 is an exploratory, single-center, double-masked, crossover design trial to 
assess the safety and tolerability of reproxalap compared to Xiidra® in subjects with Dry 
Eye Disease (DED). The clinical trial will consist of 3 visits to the clinic over a period of 
approximately 34 days. This study will be an investigator-initiated trial. 
Study Products 
and Treatment 
Treatment Products 
Product A: 0.25% Reproxalap Ophthalmic Solution (reproxalap) (Manufactured by 
Aldeyra Therapeutics, Inc.) 
Product B: Xiidra® (5% lifitegrast ophthalmic solution) 
 
 
Treatment products (reproxalap or Xiidra®) will be dosed topically in both eyes and 
administered once (1 drop in each eye) approximately 5 minutes prior to dry eye 
chamber (DEC) entry. 
Route of 
Administration 
Ophthalmic (topical ocular administration of eye drops) 
Study Population 
Approximately 50 subjects with DED, ages 18 to 70 years, are expected to be enrolled 
in the trial. The study will consist of 1 treatment group. 
Study Conduct 
The clinical trial will consist of 3 visits. At each visit, staff will update the subjects’ 
concomitant medication and collect AEs. A urine pregnancy test will be administered to 
all female subjects. Coronavirus Disease 2019 (COVID-19) screening questionnaire, 
oral temperature and COVID-19 rapid test will be performed at Visits 1, 2 and 3. Eligibility 


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criteria will be reviewed. There will be at least 7 days of washout period following Visits 
1 and 2. 
I. Medical Screening- Visit 1 (Day -21 to -8) 
All subjects will undergo a medical screening visit (Visit 1), including written informed 
consent, demographics, medical/medication and ocular history. Intraocular Pressure 
(IOP) will be performed prior to DEC entry. SVA and SLE will be performed prior to DEC 
entry. Symptom questionnaires (Ocular Discomfort Score, Ocular Itching Score) will be 
performed approximately 15 minutes pre-saline dose and approximately every 5 (+2) 
minutes while in the DEC. Saline will be administered in the clinic approximately 5 
minutes prior to DEC entry. Following DEC exit (approximately 45 minutes), SVA 
(EDTRS), and SLE will be performed following chamber exit. Dilated fundoscopy will be 
performed post-DEC after SVA and SLE. After at least 7 days of washout, subjects will 
return for Visit 2. 
II. Treatment- Visit 2 (Day 1 + 2) and Visit 3 (Day 8 + 2) 
A fixed treatment sequence is allotted for Visit 2 and 3. SVA and SLE will be performed 
prior to symptom questionnaires, and eligibility criteria will be reviewed. Symptom 
questionnaires (Ocular Discomfort Score and Ocular Itching Score) will be performed 
approximately 15 minutes pre-dose and approximately every 5 (+2) minutes while in the 
DEC. Test product will be administered in the clinic approximately 5 minutes prior to 
chamber entry. Subjects will be exposed to a DEC (approximately 45 minutes) with 
Ocular Discomfort Score and Ocular Itching Score assessments every 5 (+2) minutes. 
SVA (EDTRS) and SLE will also be performed following DEC exit. There will be at least 
7 days of washout after Visits 1 and 2. Dilated fundoscopy will be performed post-DEC 
after SVA and SLE at Visit 3. 
Inclusion Criteria 
1. Eighteen (18) to 70 years of age at the time of screening (either gender and any 
race). 
2. Ability to provide written informed consent. 
3. Reported history of dry eye for at least 6 months prior to Visit 1. 
4. Reported history of the use of eye drops within 6 months but not within 2 weeks of 
Visit 1. 
5. 
 
 
 
 
Exclusion Criteria 
1. 
Clinically significant slit-lamp, IOP, dilated fundoscopy and SVA findings at Visit 1 
that may include active blepharitis, severe meibomian gland dysfunction, lid margin 
inflammation, glaucoma and any other retinol disorders or active ocular allergies 
that require treatment, or in the opinion of the Investigator may interfere with study 
parameters including inactive viral infections or history of inflammatory disease 
(except Dry Eye Disease). 
2. 
Diagnosis of an ongoing ocular infection (bacterial, viral, or fungal) or active ocular 
inflammation at Visit 1. 
3. 
Contact lens use within 7 days of Visit 1 or anticipate using contact lenses during 
the trial. 


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4. 
Previously had laser-assisted in situ keratomileusis (LASIK) surgery within 12 
months of Visit 1 and/or planned ocular and/or lid surgeries over the study period 
or any other ocular surgery within 6 months of Visit 1. 
5. 
Systemic corticosteroid or other immunomodulatory therapy (not including inhaled 
corticosteroids) within 60 days of Visit 1 or any planned immunomodulatory therapy 
throughout the study period. 
6. 
Temporary punctal plugs during the study that have not been stable within 30 days 
of Visit 1. 
7. 
Eye drop use within 2 weeks of Visit 1 and/or an unwillingness to discontinue any 
topical ophthalmic prescription or over-the-counter solutions, artificial tears, gels, 
or scrubs for the duration of the trial (excluding medications allowed for the conduct 
of the trial). 
8. 
Corrected SVA greater than or equal to 20/50 measured binocularly at Visit 1 
before DEC. 
9. 
Women of childbearing potential (WOCBP) who are pregnant, nursing, or not using 
an effective means of contraception. All female subjects must have a negative 
pregnancy test at Screening and Visits 2 and 3. 
10. If of childbearing potential (female or male), unwillingness to use 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 a 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 
trial.) 
11. Known allergy and/or sensitivity to the test article or its components. 
12. A condition that 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 trial. 
13. Current enrollment in an investigational drug or device study or has used an 
investigational drug or device within 30 days of Visit 1. 
14. Xiidra® (lifitegrast ophthalmic solution) use within 1 year of Visit 1. 
15. Reproxalap ophthalmic solution study participation within 1 year of Visit 1. 
16. Current use of 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. 
17. Inability or unwillingness to follow instructions, including participation in all study 
assessments/procedures and visits. 
18. Antihistamine  use within 1 week prior to Visit 1. 
19. COVID-19 vaccine administration within 3 days prior to Visit 1. 
20. Positive COVID-19 test within 4 weeks prior to Visit 1. 
Statistical 
Analysis 
Due to the exploratory nature of the study statistical analysis will be performed as 
required. 


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Safety Analysis 
Safety analysis will include descriptive analysis and listings according to received 
treatment. Safety analysis will be performed on all subjects receiving at least one dose 
of study medication. Subject’s safety data will be presented according to the treatment 
they actually received. The Safety population will be used for all analyses of safety 
endpoints as well as demographics and baseline characteristics. 


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5. 
STUDY SCHEMATIC  
Table 5.1-1: Schedule of Assessments 
Procedure 
Visit 1 
Day –21 to -8 
Screening/Baseline 
Visit 2 
Day 1 + 2 
Randomization/ 
Dry Eye Chamber 
Visit 3 
Day 8 + 2 
Dry Eye Chamber 
COVID-19 screening questionnaire, oral temperature and COVID-19 rapid 
test 
X 
X 
X 
Informed Consent  
X 
 
 
Demographics 
X 
 
 
Medical/Medication & Ocular History 
X 
 
 
Medical/Medication Update 
 
X 
X 
Urine Pregnancy Test (for all female subjects) 
X 
X 
X 
Dry Eye Chamber1 
X 
X 
X 
Symptom Questionnaires (Ocular Discomfort Score/Ocular Itching Score)2 
X 
X 
X 
Inclusion/Exclusion Criteria Review 
X 
X 
X 
Snellen Visual Acuity3 
X 
X 
X 
Slit-lamp Examination3 
X 
X 
X 
Saline Instillation 
X 
 
 
Intraocular Pressure (IOP) 
X4 
 
 
Dilated Fundoscopy 
X5 
 
X5 
Randomization 
 
X 
 
Test Article Instillation 
 
X 
X 
Adverse Event /Concomitant Medication Query 
X 
X 
X 
Study Exit 
 
 
X 
1Dry eye chamber exposure (approximately 45 minutes). 
2Will be performed within approximately 15 minutes prior to the entry and every 5+2 minutes while in the chamber. 
3Will be performed pre-chamber (prior to symptom questionnaires) and post-dry eye chamber. 
4Will be performed prior to dry eye chamber entry. These tests will be performed prior to symptom questionnaires. 


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5Will be performed post-DEC after SVA and SLE 
 
Note:  
1. A washout period of at least 7 days following visits 1 and 2 is given in this study. 
2. 
 training will be provided to the study participants at Visit 1, 2 and 3. 
 
 
 
Table 5.1-2: Schedule of Subject Assessed Ocular Discomfort/Ocular Itching  
Time points in minutes  
0 
5 
10 
15 
20 
25 
30 
35 
40 
45 
Window (minutes) 
-15 
+2 
Visit 1, 2 and 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Endpoints 
5.1.1 Exploratory Endpoints 
• 
Change in ocular discomfort score (0-10) from baseline over 45 minutes in the dry eye 
chamber 
• 
Change in ocular itching score (0-10) from baseline over 45 minutes in the dry eye 
chamber 
5.1.2 Safety Endpoints 
The safety endpoints are as follows: 
• 
Snellen visual acuity (SVA) 
• 
Slit-lamp examination (SLE) 
• 
Adverse event (AE) query 
6. 
INTRODUCTION 
 
Background and Study Rationale 
Dry eye disease (DED) is a common, multifactorial tear film and ocular surface disorder that 
causes eye pain and vision impairment. DED, also called keratoconjunctivitis sicca, is 
characterized by several symptoms of ocular discomfort, including but not limited to dry eye 
sensation, foreign body sensation, irritation, burning, tearing, ocular pain, and itching. Patients 
with DED may experience significant ocular discomfort and reduced visual function, resulting in a 
decreased quality of life or work productivity.1 DED is a globally prevalent disease that 
disproportionately affects older individuals (>50 years) and women. According to the Dry Eye 
Workshop II report, DED prevalence ranges from 5-50% worldwide, while several studies 
estimate prevalence in the 20–30% range, notably among individuals over 50 years old. The Dry 
Eye Workshop II meta-analysis corroborated prior findings that prevalence rises with age and is 
more prevalent in women than males. Dry eye symptoms were reported by 28.7% of surveyed 
patients in optometric clinics in the 1997 Canada Dry Eye Epidemiology Study (CANDEES). 
According to a recent survey, 21.3 percent of Canadians aged 18 and up have DED. 2,3 
For short-term treatment of DED, doctors typically give artificial tear eye drops and topical 
corticosteroids. Antibiotics (tetracyclines and macrolides), nonsteroidal anti-inflammatory drugs, 
autologous serum drops, omega fatty acids, mucin secretagogues, and anti-inflammatory drugs 
are used to treat DED symptoms. In addition, individuals with chronic DED are increasingly being 
prescribed prosthetic scleral lenses (i.e. PROSE) that also function as additional tear reservoirs 
to improve ocular surface hydration. Meibomian gland dysfunction, a major cause of evaporative 
dry eye illness, is frequently treated with hot eyelid compresses. Punctual plugs can be used to 
stop tear outflow in advanced cases of DED. To minimize tear evaporation in extreme cases of 
dry eye, tarsorrhaphy surgery, tear duct cauterization, or amniotic membrane transplantation may 
be required.4, 5 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Given 
the severity, frequency, and complexity of DED, as well as the restricted modes of action by which 
these two compounds treat dry eyes, there is a medical need for more dry eye therapies, 
particularly those with multiple modes of action that target a larger dry eye population and are 
effective and safe for long-term daily usage.6,7 
Reproxalap is a novel, first-in-class aldehyde sequestering agent that binds rapidly and 
irreversibly to pro-inflammatory reactive aldehyde species (RASP). Topical ocular reproxalap has 
demonstrated clinical activity in Phase 2 and Phase 3 clinical trials in non-infectious anterior 
uveitis,8 allergic conjunctivitis,9 and DED.10, 11 Reproxalap has been administered to more than 
1200 subjects with no clinically significant safety concerns.  
Reproxalap topical ophthalmic solution is formulated as a sterile, preservative-free, aqueous 
solution for topical ocular delivery. Subjects are expected to self-administer 1 drop of 0.25% 
Reproxalap Ophthalmic Solution (reproxalap) or Xiidra® (5% lifitegrast ophthalmic solution). 
Direct instillation is the most efficient method for delivery to the ocular surface and is an accepted 
and widely used method for topical application to the eye. This exploratory study will examine 
tolerability and activity of 0.25% Reproxalap Ophthalmic Solution versus Xiidra® dosed once prior 
to entering dry eye chamber (DEC) in subjects with DED.12  
 
Nonclinical Data 
Inhibition of RASP by reproxalap has been studied under various in vitro conditions in which 
reproxalap has been shown to rapidly and irreversibly bind several common pro-inflammatory and 
cytotoxic RASP. The data suggest that RASP preferentially form covalent adducts with reproxalap 
under conditions that may mimic the physiologic milieu.  
Reproxalap has been well-tolerated in multiple non-clinical single-dose and repeat-dose 
pharmacology and toxicology studies in mice, rats, rabbits, dogs, and non-human primates, via 
topical ocular, intravitreal, topical dermal, oral, intraperitoneal, subcutaneous, and intravenous 
routes of administration. In a standard battery of genotoxicity tests, reproxalap was non-
mutagenic and non-clastogenic. Furthermore, no adverse effects of reproxalap were evident in in 
vivo central nervous system, respiratory, and cardiovascular safety pharmacology studies.  
Non-clinical pharmacokinetic studies have shown that topical ocular administered reproxalap is 
absorbed rapidly into ocular tissue and delivers potentially therapeutically relevant concentrations 
of reproxalap to the eye's anterior chamber while resulting in minimal systemic exposure.  
Overall, the non-clinical data suggest that reproxalap administered as a topical ophthalmic 
solution will continue to be safe, well-tolerated, and effective in clinical testing.12  
 
Effects in Humans 
Reproxalap topical ophthalmic solution has been investigated in one healthy normal volunteer 
clinical trial (NS2-001) and thirteen clinical trials across three ocular indications. Six clinical trials 
were conducted in subjects diagnosed with allergic conjunctivitis, ranging from Phase 1/2 to 
Phase 3 (ALD NS2-203-D1, ADX-102- AC-004, ADX-102-AC-008, ADX-102-AC-010, and ADX-
102-AC-011, ADX-102-AC-017). One Phase 1 tolerability trial (ADX-102-DED-018), three Phase 


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2 trials (ADX-102-DES-007, ADX-102-DED-009, and ADX-102-DED-013), and one Phase 3 trial 
(ADX-102-DED-012) were conducted in subjects with DED. A Phase 2 clinical trial (NS2-02) and 
a Phase 3 trial (ADX-102-UV-005) were conducted in subjects with non-infectious anterior uveitis. 
In Phase 1 clinical trials, reproxalap was safe and well-tolerated. In all Phase 2 and 3 clinical trials, 
reproxalap was safe and well-tolerated, and consistently demonstrated statistically significant 
improvement from baseline or statistically significant improvement over the vehicle.12  
 
Benefit/Risk Assessment 
No clinically significant safety signals have been observed in more than 1200 subjects treated 
with topical ocular reproxalap. Generally, mild and transient instillation site discomfort is the most 
commonly reported adverse event. The acute tolerability of topical ocular reproxalap 
administration was characterized in two clinical trials where drop comfort was assessed and 
symptoms recorded within minutes of dosing. 
 
 
 
Similarly, ADX-102-AC-011 and ADX-102-AC-017 compared 0.25% reproxalap to the vehicle 
during peak symptomatology in an allergen chamber and indicated that reproxalap was 
statistically superior to the vehicle as soon as five to ten minutes after administration. 
 
 
 
 
  
 
Rationale for Dose Selection 
Ophthalmic dosing is the optimal route of administration for ocular allergy treatments. The dosage 
and dosage regimen was selected based on previous data from non-clinical and clinical studies. 
0.25% reproxalap is the intended commercial formulation for allergic conjunctivitis and DED, and 
is now in Phase 3 clinical testing for DED. 
7. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
To explore the safety and tolerability of reproxalap compared to Xiidra® in a dry eye chamber. 
8. 
STUDY DESIGN 
 
Overall Study Design 
C1D01056 is an exploratory, single-center, double-masked, crossover design trial to assess the 
safety and tolerability of 0.25% Reproxalap Ophthalmic Solution (reproxalap) compared to 
Xiidra® (5% lifitegrast ophthalmic solution) in subjects with DED.  
 
 
 
 
 
 
The DEC can exacerbate the signs and symptoms of dry eye in 


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subjects with dry eye.  The controlled environment, over time, allows evaluation of subject 
responses at any time point throughout the chamber session. 
Subjects will be administered with the following: 
Product A: 0.25% Reproxalap Ophthalmic Solution (reproxalap) administered 1 drop in each eye 
approximately 5 minutes prior to DEC entry. 
Product B: Xiidra® (5% lifitegrast ophthalmic solution) administered 1 drop in each eye 
approximately 5 minutes prior to DEC entry. 
This study will include 3 clinic visits over a period of approximately 34 days. 
At Visit 1 Screening (Days -21 to -8), subjects who meet screening inclusion/exclusion criteria will 
be treated with 1 drop of saline in each eye. At Visit 2, (Day 1), subjects who continue to meet 
inclusion/exclusion criteria will be eligible to receive test products as described above. 
At Visits 1, 2 and 3, assessments of ophthalmic evaluations will be collected 
 
. In the event of an 
 failure, paper diary 
cards will be used as a backup to collect symptom scores. Ocular Discomfort Score (0 – 10) and 
Ocular Itching Score (0 to 10) will be employed for subject-reported symptoms of ocular 
discomfort and ocular itching, respectively. For each scale, 0 is no symptomatology and 10 is 
maximum symptomatology. 
Ocular activity will be assessed by symptom questionnaires (Ocular Discomfort Score/Ocular 
Itching Score). Safety will be assessed before and after chamber exposure by SVA testing and 
SLE. 
9. 
SUBJECT SELECTION 
 
Number of Subjects 
The total sample size will be 50 subjects. Sufficient numbers of volunteers will be screened to 
enroll 50 subjects.  
 
Inclusion Criteria for Study Volunteers 
Each subject must meet the following criteria to be eligible: 
1. Eighteen (18) to 70 years of age at the time of screening (either gender and any race). 
2. Ability to provide written informed consent. 
3. Reported history of dry eye for at least 6 months prior to Visit 1. 
4. Reported history of the use of eye drops within 6 months but not within 2 weeks of Visit 1. 
5. 
 
 
 
 
Exclusion and Restriction Criteria for Study Volunteers  
9.3.1 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded: 


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1. 
Clinically significant slit-lamp, IOP, dilated fundoscopy and SVA findings at Visit 1 that may 
include active blepharitis, severe meibomian gland dysfunction, lid margin inflammation, 
glaucoma and any other retinol disorders or active ocular allergies that require treatment, or 
in the opinion of the Investigator may interfere with study parameters including inactive viral 
infections or history of inflammatory disease (except Dry Eye Disease). 
2. 
Diagnosis of an ongoing ocular infection (bacterial, viral, or fungal) or active ocular 
inflammation at Visit 1. 
3. 
Contact lens use within 7 days of Visit 1 or anticipate using contact lenses during the trial. 
4. 
Previously had laser-assisted in situ keratomileusis (LASIK) surgery within 12 months of Visit 
1 and planned ocular and/or lid surgeries over the study period or any ocular surgery within 
6 months of Visit 1. 
5. 
Systemic corticosteroid or other immunomodulatory therapy (not including inhaled 
corticosteroids) within 60 days of Visit 1 or any planned immunomodulatory therapy 
throughout the study period. 
6. 
Temporary punctal plugs during the study that have not been stable within 30 days of Visit 1. 
7. 
Eye drop use within 2 weeks of Visit 1 and unwillingness to discontinue any topical ophthalmic 
prescription or over-the-counter solutions, artificial tears, gels, or scrubs for the duration of 
the trial (excluding medications allowed for the conduct of the trial). 
8. 
Corrected SVA greater than or equal to 20/50 measured binocularly at Visit 1 before DEC. 
9. 
Women of childbearing potential (WOCBP) who are pregnant, nursing, or not using an 
effective means of contraception. All female subjects must have a negative pregnancy test 
at Screening and Visits 2 and 3. 
10. If of childbearing potential (female or male), unwillingness to use 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 a 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 trial). 
11. Known allergy and/or sensitivity to the test article or its components (reproxalap or lifitegrast). 
12. A condition that 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 trial. 
13. Current enrollment in an investigational drug or device study or has used an investigational 
drug or device within 30 days of Visit 1. 
14. Xiidra® (lifitegrast ophthalmic solution) use within 1 year of Visit 1. 
15. Reproxalap ophthalmic solution study within 1 year of Visit 1. 


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16. Current use of 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. 
17. Inability or unwillingness to follow instructions, including participation in all study 
assessments/procedures and visits. 
18. Antihistamines use within 1 week prior to Visit 1. 
19. COVID-19 vaccine administration within 3 days prior to Visit 1. 
20. Positive COVID-19 test within last 4 weeks prior to Visit 1. 
9.3.2 Restrictions and Concomitant Medications 
Once the study has begun, the subjects will be instructed to take only the study medication(s) 
described in this protocol. If the subject takes any other medication during the study, the 
Investigator will record the necessary information. 
Table 9.3.2-1: Restrictions and Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Subjects who violate any of the above restrictions may be excluded or dropped from the study at 
the discretion of the Investigator. Individual exceptions to the above restrictions may be approved 
by the Investigator. 
9.3.3 Female Subjects of Childbearing Potential 
A female subject is considered of childbearing potential (WOCBP) if she is not post-menopausal, 
not congenitally sterile; not diagnosed as infertile (and not undergoing treatment to reverse 
infertility); or has not undergone successful surgical sterilization (such as tubal ligation, bilateral 
oophorectomy, or hysterectomy) completed at least 3 months prior to Screening. A woman is 
considered of non-childbearing potential if she is post-menopausal (if she is either amenorrheal 
for greater than 2 consecutive years, or naturally post-menopausal [no mense] for at least 1 year), 
surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy), congenital sterility, or 
diagnosed as infertile and not undergoing treatment to reverse infertility. 
WOCBP must use effective methods of birth control starting at least 4 weeks prior to the 
Screening Visit 1 and until the last study procedure, such as total abstinence, intrauterine device, 
a double-barrier method, oral, transdermal, injected or implanted non- or hormonal contraceptive. 
A sterile sexual partner is not considered an adequate form of birth control. Subjects on hormonal 
contraceptives must have been on the same hormonal contraceptive for at least one month before 
the Screening Visit 1 and continue throughout the duration of the study. 
WOCBP will be instructed to contact the Investigator immediately if they suspect they might be 
pregnant. 
9.3.4 Male Subjects  
Male subjects must commit to not father a child or donate sperm from the first dose until 3 months 
post-last dose. 
Male subjects (with female partners of childbearing potential) must commit to the consistent and 
correct use of at least two effective methods of birth control (as listed below) or total abstinence 
from the Medical Screening Visit until 30 days after the last administration of the investigational 
product. 
• 
Condom and diaphragm with spermicide (foam, cream, gel, sponge) 
• 
Condom and cervical cap with spermicide (foam, cream, gel, sponge) 
• 
Non-hormonal intrauterine device (IUD) 
Female partner(s) of male volunteers also have the option to use the following highly effective 
hormonal method of contraception: implants, injectables, combined oral contraceptives, and 
IUDs. 


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10. 
STUDY PRODUCT AND TREATMENT SEQUENCE 
 
Study Product and Treatment 
The following products will be used in the study: 
Product A: 0.25% Reproxalap Ophthalmic Solution (reproxalap) (Manufactured by Aldeyra 
Therapeutics, Inc.) administered 1 drop in each eye approximately 5 minutes prior to DEC entry. 
Product B: Xiidra® (5% lifitegrast ophthalmic solution) (Manufactured by Novartis 
Pharmaceuticals Canada, Inc.) administered 1 drop in each eye approximately 5 minutes prior to 
DEC entry.  
 
Treatment Sequence 
At Visit 1, eligible subjects will be enrolled and scheduled for Visits 2 and 3. Subjects will be dosed 
as per a fixed sequence at Visits 2 and 3. 
 
Masking and Unmasking 
10.3.1 Masking 
This is a double-masked clinical trial. The Sponsor (PI), Investigators, qualified site personnel 
(except delegated unmasked pharmacy staff), and subjects will be masked to the investigational 
product administered until database lock. Only the delegated unmasked pharmacy staff and 
Scientific Affairs staff involved with preparing the assignment of Treatment A and B to the fixed 
sequence will have access to the treatment under evaluation. 
10.3.2 Emergency Unmasking 
Emergency unmasking should only be performed when necessary to treat the subject. Most often, 
knowledge of the possible treatment assignments is sufficient to treat a clinical trial subject who 
presents with an emergency condition. 
The investigator should make every effort to contact the Medical Monitor to discuss the subject’s 
emergency and the need to unmask prior to unmasking any subject. 
In situations in which the investigator has tried but is unable to reach the Medical Monitor, best 
judgement on the part of the investigator should be used, based on the nature and urgency of the 
clinical situation, and may proceed with unmasking without having successfully reached and 
discussed the situation with the Medical Monitor. Once a subject's treatment assignment has been 
unmasked, the Medical Monitor should be notified within 24 hours of the unmasking of the 
treatment, without revealing the treatment.  
As this is a fixed sequence clinical trial, every attempt will be made to maintain the masking for 
the other subjects in the event of an unmasking must occur, an unmasking procedure will be 
developed. 
The emergency unmasking should be performed by the designated site personnel. The 
investigator must also indicate in source documents and the Case Report Form (CRF) that the 
mask was broken and provide the date, time, and reason for breaking the mask.  
Any AE or Serious Adverse Event (SAE) associated with breaking the mask must be recorded 
and reported as specified in the protocol. The investigator has the responsibility to contact the 


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Sponsor (PI) in the event of a drug-related, serious, unexpected AE, the ProPharma Group or 
designee will be provided with the treatment assignment for the subject for regulatory reporting. 
If treatment assignment is unmasked, the treatment will be discontinued immediately, and the 
subject will be discontinued from the clinical trial.  
The mask may be broken in the case of pregnancy should the subject desire this information.  
11. 
STUDY VISITS 
 
COVID-19 Screening 
The following procedures will be performed as part of COVID-19 screening: 
• 
Subjects will be pre-screened based upon a COVID-19 questionnaire at each clinic 
visit. 
• 
Body temperature will be measured at each visit. 
• 
A nasal swab will be collected for COVID-19 testing on the day of Visits 1, 2 and 3.  
Subject’s further participation in the study will be based on the COVID-19 test results and 
procedures. 
 
Visit 1: Screening (Day -21 to -8) 
The following activities will be completed at Visit 1: 
• 
Subjects will be asked to sign and date the Informed Consent Form. 
• 
Demographic data, including date of birth, age, race and ethnicity, will be recorded.  
• 
Medical/Medication and Ocular history will be completed for each subject. 
• 
A urine pregnancy test will be performed (for all female subjects). Subjects with a 
positive result will be excluded. 
• 
The subjects will be evaluated for study inclusion, exclusion and restriction criteria.  
• 
Symptom Questionnaires (Ocular Discomfort Score, Ocular Itching Score) will be 
performed within 15 minutes prior to DED entry and every 5 +2 minutes up to 45 
minutes while in the chamber. 
• 
An SVA and SLE will be performed pre and post-DEC. 
• 
IOP will be performed prior to DEC entry and dilated fundoscopy will be performed 
post-DEC. 
• 
Saline will be administered in the clinic approximately 5 minutes prior to the DEC entry.  
• 
DEC session (approximately 45 minutes). 
• 
Adverse events and concomitants medications will be recorded before the subject 
leaves the site. 
• 
After 7 ± 1 day of washout period, eligible subjects will come to Visit 2 


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Visits 2 (Day 1 + 2) and 3 (Day 8 + 2): Treatment/Dry Eye Chamber 
Eligible subjects will return for 2 treatment visits. The treatment visits will occur following at least 
7 days after visits 1 and 2. At Visit 2 the subjects will be randomized to receive one of the 2 
treatment sequences as mentioned in Section 10.2. At Visits 2 and 3, the following activities will 
be performed: 
• 
Medical/medication and ocular history will be updated for each subject. 
• 
A urine pregnancy test will be performed (for all female subjects). Subjects with a 
positive result will be excluded. 
• 
The subjects will be evaluated for study inclusion, exclusion and restriction criteria.  
• 
An SVA and SLE will be performed pre and post-DEC. 
• 
Symptom questionnaires (Ocular Discomfort Score, Ocular Itching Score) will be 
performed within 15 minutes prior to study treatment administration and approximately 
every 5 minutes while in the chamber. 
• 
Test product will be administered in the clinic approximately 5 minutes prior to the 
DEC entry. 
• 
 DEC session (approximately 45 minutes). 
• 
Dilated fundoscopy will be performed post-DEC after SVA and SLE at Visit 3. 
• 
Adverse events and concomitants medications will be recorded before the subject 
leaves the site. 
• 
Study exit (Visit 3). 
 
Phone call follow-up 
For any subjects who withdraw prior to study exit, there will be a phone call within 7(+3) days to 
follow up on the subject’s health. 
12. 
STUDY ASSESSMENTS AND PROCEDURES 
 
Efficacy Assessments 
12.1.1 Ocular Discomfort Score and Ocular Itching Score 
Ocular discomfort score and ocular itching score will be measured within 15 minutes before 
chamber entry and over 45 minutes (every 5 minutes) in the DEC. The ocular discomfort score is 
a participant-reported symptom index (0 to 10 scale; 0 represents no discomfort, 10 represents 
maximum discomfort). Ocular itching score is a participant-reported symptom index (0 to 10 scale; 
0 represents no itching, 10 represents maximum itching). The assessments of ophthalmic signs 
and symptoms will be self-administered by subjects using an electronic P
 
.
 


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Safety Assessments  
For details regarding the timing of procedures, refer to Table 5.1-1. 
12.2.1 Snellen Visual Acuity (SVA) 
SVA is a widely used metric for assessing the visual function that is sensitive to ophthalmic, 
retinal, and brain diseases. SVA chart contains lines, and each line contains five Sloan letters; 
the lines are all of the identical complexity, and the letter sizes increase geometrically from line to 
line. Each line on the chart has a similar assignment, with the font size being the only difference. 
Right and left eyes are tested using charts with distinct letter sequences. SVA will be measured 
at Visits 1, 2, and 3 as per the site’s Standard Operating Procedure (SOP). 
12.2.2 Slit-lamp Exam (SLE) 
The slit-lamp will be placed in front of the subject’s eyes and a narrow beam of bright light from 
the slit-lamp is directed into the eye. SLE observations will be graded as “normal” or “abnormal.” 
Abnormal findings will be categorized as clinically significant or not. The cornea, conjunctiva, 
anterior chamber, lens, and eyelid will be examined. Slit-lamp Exam will be conducted at Visits 1, 
2, and 3 as per the site’s Standard Operating Procedure. 
12.2.3 Intraocular Pressure (IOP) 
The fluid pressure inside the eye is commonly known as IOP. IOP will be measured using non-
contact tonometry at Visits 1as per the site’s Standard Operating Procedure. 
12.2.4 Dilated Fundoscopy 
Examining the fundus is an effective strategy to acquire a sense of the subject total vasculature. 
The investigator or qualified staff will perform a dilated fundoscopy to evaluate clinically significant 
fundus abnormalities and vitreous pathology. Dilated fundoscopy will be performed at Visit 1 and 
3 as per the site’s Standard Operating Procedure. 
Safety measurements may be obtained at the discretion of the Investigator in addition to the safety 
assessments described in this section. 
12.2.5 COVID-19 Test (SARS-CoV-2) 
At Visits 1, 2, and 3, a nasal swab will be collected at the clinical site for Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2). Subjects with a positive test result will be 
excluded/withdrawn from the study. 
12.2.6 Demographics and Medical/Medication and Ocular History 
The demographic data and a complete medical/medication and ocular history will be recorded at 
the Screening Visit. The following demographic information will be recorded: date of birth, gender, 
race, ethnicity, height, and weight. 
12.2.7 Adverse Event Query/Concomitant Medication Query 
The staff will record all adverse events observed, queried, or spontaneously volunteered by the 
subjects. An adverse event query will be performed as scheduled as per Investigator’s direction 
throughout the post-dose confinement period, prior to being released from confinement, and at 
each return visit for the study (if applicable). Subjects will be asked non-leading questions such 


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as “How do you feel now?”, “How have you felt since last asked?” or “Have you taken any 
medication since last asked?” If the presence of any symptom(s), adverse event(s), and/or 
concomitant medication is recorded, the clinical staff may advise the subjects to remain at the 
clinic site for safety reasons until the Investigator decides it is safe for the subjects to leave. If the 
subject decides to leave despite the Investigator's advice, he/she will be asked to sign a waiver. 
13. 
ANALYSES AND REPORTS 
 
Final Integrated Report 
A final integrated report will be issued to the Sponsor (PI) by Cliantha Research, which will be 
reviewed and released by Cliantha Quality Assurance (QA). It will contain a narrative description 
of the clinical and statistical procedures used during the conduct of the study. Appropriate tables 
and graphs will be created to summarize the data. 
The regulatory agency for submission will be Health Canada. The final integrated report may also 
be included in submissions to other international regulatory agencies. 
14. 
STATISTICAL CONSIDERATIONS 
 
Statistical Analyses 
Due to the exploratory nature of the study, statistical analysis will be performed as required. 
 
Safety Analysis 
Safety analysis will include descriptive analysis and listings according to received treatment. 
Safety analysis will be performed on all subjects receiving at least one dose of study medication. 
Subject’s safety data will be presented according to the treatment they actually received. The 
Safety population will be used for all analyses of safety endpoints as well as demographics and 
baseline characteristics. 
Adverse events and SAE will be classified using standard Medical Dictionary for Regulatory 
Activities (MedDRA) terminology Version 23.1 and presented by the treatment group. Summary 
tables listing the type, date of onset, date and time of resolution, incidence, severity, outcome, 
action taken, and Investigator’s opinion of relationship to the study product will be presented by 
treatment group for AEs reported after randomization. 
Concomitant medication used during the study will be listed by treatment and subject. 
 
Interim AnalysesNo interim analysis is planned at this point.  
 
Sub-group Analyses 
No sub-group analysis is planned at this point. 
15. 
ADMINISTRATIVE STUDY RECORDS 
 
Subject Enrollment and Identification  
Participants will be enrolled in the study prior to any screening procedures being performed. All 
participants will be assigned a unique subject identification number. This number will be used to 
identify their records until they are randomized into a fixed treatment sequence. Participants who 


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are randomized into the study will be assigned a unique randomization number which will be used 
to identify their records post-randomization. 
 
Study Charts/Records and Source Documents 
A study chart/record will be maintained on-site for each subject to file records such as general 
observations, medical and medication use history, physical examination, clinical laboratory data 
source documents and related documentation. The original record will be considered the data 
‘source document’. The source documents will be available for inspection (direct/remote) by the 
study monitors and/or representatives before, during, or upon completion of the study. Good 
documentation practices will be followed for source documentation. All corrections will be dated 
and initialled. The Investigator will retain the originals. 
All clinical study data not available via electronic source will be collected by the Investigator and 
staff and recorded on source documents. The Investigator will assume responsibility for ensuring 
the completeness and accuracy of all clinical documents. 
This clinical trial will be conducted, and the data will be generated, documented (recorded), and 
reported in compliance with the protocol, GCP standards, ICH and other applicable local laws and 
regulations. 
All Cliantha Research staff will be appropriately trained to ensure the collection of accurate, 
consistent, complete, and reliable data are entered onto an electronic case report form (eCRF) 
unique for each subject. 
All data collected in the study will be captured and maintained in a secure and validated electronic 
data capture (EDC) system. Cliantha Research staff will enter the data for each subject into an 
eCRF with the exception of the data collected in an electronic or paper source (e.g., lab data, 
diary data, etc.). Data source will be described in the Data Management Plan (DMP). 
The eCRF and/or diaries will contain edit checks and/or controls to ensure the quality, integrity, 
accuracy and completeness of the data entered. The Medical Monitor (medical representative) 
may examine eCRF and diary data for preliminary medical review (direct/remote). 
The eCRF data will be maintained in a validated study database with an audit trail of all changes 
that are made to the database, including the reason for the data change. AEs will be coded using 
a standard dictionary, Medical Dictionary for Regulatory Activities 
, while 
concomitant medications will be categorized using the World Health Organization Drug Dictionary 
(the most updated version of the dictionary) at the start of the study. 
Creation and validation of the EDC system and management of the data will be conducted in 
accordance with Title 21 of the Code of Federal Regulations (CFR) Part 11 and the FDA Guidance 
for Industry on Computerized Systems Used in Clinical Investigations. Methods used to ensure 
the quality and integrity of the data will be documented in the DMP, which will be approved by the 
Data Management provider and the Sponsor (PI). 


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Retention and Availability of Investigational Records 
All drug accountability records, CRFs, source data and related regulatory documents must be 
retained for at least 25 years following completion of the clinical trial. 
16. 
DRUG ACCOUNTABILITY 
All study product receipt, inventory, dispensing, dosing, and reconciliation records will be 
maintained in compliance with federal regulations. The study product will be dispensed to qualified 
study subjects according to established procedures.  
 
Product Shipment 
The drug supplies for this study will be shipped to: 
 
  
 
 
 
  
 
 
Product Receipt 
Upon receipt of drug supplies, the Investigator or designee will conduct an inventory and record 
the date received and the amount of drug received. If multiple containers of the test and/or 
reference products are received, the products will be randomized to dispensing inventory. 
 
Product Storage 
 
 
The Investigator will be responsible for maintaining accurate records of drug 
receipt, dispensing, and return. At the end of the study, all partially used and unused study 
products will be stored or disposed of as determined and agreed upon by the Sponsor (PI) and 
. 
 
Drug Dose Package Labeling 
The study medication will be dispensed in individual subject’s kits and labeled with study-specific 
labels. Labels will reflect the use for the investigational purpose only, plus a unique number that 
will be used to assign the medication to the subject according to their randomized treatment 
assignment. 
17. 
SUBJECT SAFETY MONITORING AND ADVERSE EVENTS 
 
Subject Safety Monitoring  
Study staff will monitor the subjects throughout the study. Between the time interval of the study 
periods, staff will be available for subject queries. An Investigator will be on-site for dosing and 
on-call throughout the duration of the study. 


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The Sponsor (PI) will designate qualified individuals to maintain a close liaison with the 
Investigator and study staff to ensure the clinical investigation follows the approved protocol and 
the research intent of GCP. Internal SOP for compliance with applicable government regulations 
will also be applied. This liaison will be documented by personal and/or telephone visits prior to 
study initiation and during the study to enable periodic reviews as well as clarify any questions, 
which may arise during the study. During on-site visits, Sponsor (PI) study monitors will be 
provided access to all study source documents to ensure the integrity of the data. Direct/remote 
access to such data during the inspection or audits/monitoring of the study will be provided to 
IRB, Sponsor (PI)/ his representatives and regulatory authorities, but they must agree to respect 
the confidentiality of the data. 
17.1.1 Pregnancy 
Any female with a confirmed positive pregnancy result during study participation (from the time of 
signing the informed consent form until the end of the study) will be excluded from the study or 
immediately withdrawn from the study. Because of the possibility that the fetus/embryo could have 
been exposed to the study drug through the parent and for the subject safety, the subject will be 
followed until the end of the pregnancy (including spontaneous or voluntary termination). 
If a subject becomes pregnant or suspects that they became pregnant during the study or within 
30 days after the study is complete, they must notify the clinical site. 
The pregnancy will be recorded on a Pregnancy form (provided by the clinical site) and reported 
to ProPharma Group and IRB. In the absence of a pregnancy form, an adverse event form can 
be used. 
Attempts to contact the subject to inquire about the status and progression of the pregnancy will 
be made at intervals deemed appropriate (e.g., at least every three months) until an outcome of 
the pregnancy is known. This contact will be documented. 
 
 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug-related. AEs may include any changes in 
physical examination or laboratory parameters that are, in the Investigator's opinion, clinically 
significant changes.   
An SAE is defined as any AE that, in the view of either the Investigator or Sponsor (PI), results in 
any of the following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
In-patient hospitalization or prolongation of existing hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 


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Important medical events that may not result in death be life-threatening or require hospitalization 
may be considered an SAE when based upon appropriate medical judgment. They may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.   
Life-threatening AE: 
Any AE that places the subject, in the view of either the 
Investigator or Sponsor (PI), at immediate risk of death. It does 
not include an AE that, had it occurred in a more severe form, 
might have caused death. 
Unexpected AE: 
Any AE not listed in the applicable product information (e.g., drug 
product label or Investigator’s brochure) or that is not listed at the 
specificity or severity that has been observed.  
"Unexpected," as used in this definition, also refers to AEs that are mentioned in the applicable 
product information 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. If such an unexpected AE is suspected to be related to the drug, then it is 
known as “Suspected Unexpected Serious Adverse Reactions (SUSARs)”. 
17.2.1 Recording Adverse Events 
The staff will record all AEs observed, queried, or spontaneously volunteered by the subjects 
(regardless of seriousness or relationship to study treatment) in the appropriate section of the 
subject’s case report form or source documents. Subjects experiencing AEs (including those 
withdrawn from the study due to an AE) will be followed until recovery to a satisfactory state, or 
stabilization, or appropriate outcome is established as judged by the Investigator. Exacerbation 
of conditions related to the signs and symptoms of Dry Eye will not be reported as an AE.  
 
The following details will be recorded for AEs: 
• 
Description of event/symptom 
• 
Onset date and time of event 
• 
End date and time of event 
• 
Maximum severity/intensity rated as follows: 
Mild: 
Causing no limitation of usual activities, the subject may 
experience slight discomfort. 
Moderate: 
Causing some limitation of usual activities, the subject may 
experience annoying discomfort 
Severe: 
Causing inability to carry out usual activities, the subject may 
experience intolerable discomfort or pain 
• 
Action taken with study treatment noted as follows: 
 
Dose not changed 


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Dose reduced 
 
Drug interrupted 
 
Drug withdrawn 
 
Not applicable 
 
Unknown 
• 
Any other action taken (such as concomitant medication, non-drug therapy, hospitalization 
or none) 
• 
Outcome of AE noted as follows:  
 
Fatal 
 
Not recovered/not resolved 
 
Recovered/resolved 
 
Recovered/Resolved with sequelae 
 
Unknown 
• 
Causality noted as follows: 
Related: 
A causal relationship between the study treatment and the 
AE is a reasonable possibility. 
Not Related: 
A causal relationship between the study treatment and the 
AE is not a reasonable possibility. 
 
17.2.2 Reporting Serious Adverse Events 
AEs and medical history will be coded and classified according to the MedDRA, and AEs will be 
reported with respect to severity, duration, relationship to study drug(s) and action taken. 
Concomitant medications will be categorized using the World Health Organization Drug Dictionary 
(the most updated version of the dictionary) at the start of the study. 
All serious adverse experiences, whether deemed drug-related or not, will be reported to 
ProPharma Group preferably by email (or by telephone if email is not possible) immediately after 
the awareness by Investigator and in no case later than 24 hours, followed by a written report 
within 2 working days. The investigator is responsible for following all local regulations for the 
reporting of safety information, including the reporting of SAEs to their local IRB/Research Ethics 
Board (REB)/Independent Ethics Committee (IEC). 
The investigator must promptly report to his or her local IRB/REB/IEC all unanticipated problems 
involving risks to subjects. This includes death from any cause and all serious adverse events 
reasonably or possibly associated with the use of the investigational product.  


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The Sponsor (PI) or their designee is responsible for appropriate reporting of relevant AEs, 
suspected unexpected serious adverse reactions (SUSARs) involving investigational product, to 
all regulatory authorities as per the below timeline:  
• 
When neither fatal nor life-threatening, within 15 days after becoming aware of the 
information 
• 
When fatal or life-threatening, immediately when possible and, in any event, within seven 
(7) days after becoming aware of the information 
• 
Within eight (8) days after having informed Health Canada of the adverse drug reaction, 
submit a report that includes an assessment of the importance and implication of any 
findings 
In addition, the Sponsor (PI) or designee will be responsible for the submission of safety letters 
(e.g., SUSARs) to the central IRB/REB/IEC and participating investigators of all SUSARs 
involving IP according to applicable regulations.  
After termination of the clinical trial (determined as last subject, last visit), any unexpected safety 
issue that changes the risk-benefit analysis and is likely to have an impact on the subjects who 
have participated in it will be reported by the Sponsor (PI) as soon as possible to the competent 
authority (ies) concerned together with proposed actions. 
 
The following Sponsor representative is to be contacted immediately following the occurrence of 
an SAE: 
 
Phone: 
 
Email: 
  
 
17.2.3 Removal of Subjects from Study  
Subjects will be advised that they are free to withdraw from the study at any time for any reason 
or, if necessary, the Investigator may withdraw a subject from the study to protect the health of 
that subject. A subject may also be withdrawn for not complying with study procedures. The 
clinical report will include all reasons for early withdrawals. 
All subjects who receive at least one dose of either of the study products will be included in the 
safety analysis. If a subject terminates from the study early, all efforts will be made to complete 
all applicable safety procedures. In case of early termination, the Investigator will fully document 
the reason for early termination. Reasons for the early termination may include the following: 
• 
Voluntary withdrawal by subject. 
• 
Significant AE that led the Investigator or subject to withdraw for safety reasons. 


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• 
Non-compliance with protocol requirements (e.g., use of restricted medication, not 
following dosing procedures, failure to make scheduled study visits in a timely 
fashion). 
• 
Pregnancy 
• 
Participant enrolls in another clinical trial or is found to have previously enrolled in 
this clinical trial. 
• 
Positive COVID-19 test result. 
 
17.2.4 Termination of Study Due to Adverse Events 
If, in the opinion of the Sponsor (PI), Regulatory authorities or the IRB, the incidence and severity 
of AE(s) outweighs the benefit of continuing the study, the study may be terminated.  
18. 
ETHICS OF CONDUCT 
This study will be conducted in compliance with the protocol and accordance with the appropriate 
guidelines and all applicable federal government codes, acts and regulations, the ethical 
principles that have their origins in the Declaration of Helsinki and all amendments, Good Clinical 
Practice (GCP) requirements, the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidance E6 (R2), and Tri-Council Policy 
Statement (Canada). Protocol and Informed Consent approval by the Ethics Board will be sought 
prior to the commencement of the study, and a copy of the Ethics attestation will be sent to the 
Sponsor (PI).   
19. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Cliantha Research will implement and maintain quality control procedures to ensure that the study 
is conducted and that the data are generated, documented, and reported in compliance with the 
protocol, GCP and applicable regulatory documents. 
• 
All participant data relating to the study will be recorded on electronic CRF unless transmitted 
to the Sponsor (PI) or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct/remote access to source data documents. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol, written SOPs, study-


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specific plans and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Separate risk management plan will be developed prior to the start of the study in accordance 
with ICH E6 (R2). 
 
Pandemic COVID-19 Response Plan 
Regulatory authorities have recognized that the Coronavirus Disease 2019 (COVID-19) pandemic 
may impact the conduct of the clinical study. COVID-19 pandemic has created a lot of uncertainty 
in the current situation and has put the subject’s safety, protocol compliance and data validity at 
high risk. 
Due to the COVID-19 pandemic, challenges may arise for clinical study conduct, for example, 
quarantines of site personnel/study participants, travel limitations, interruptions to the supply chain 
for the IP(s), or other considerations if site personnel or study participants become infected with 
COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures, 
including administration or use of the investigational product, housing duration or adhering to 
protocol specified visits and laboratory/diagnostic testing.  
To accommodate these challenges and mitigate safety risks associated with COVID-19, changes 
may be required from approved protocol which includes (but not limited to) conducting the study 
in multiple groups, change in study procedures timing, change in subject’s housing duration; 
ambulatory visits, additional test or parameter may be performed to standard inclusion or exclusion 
criteria at the discretion of Investigator/designee, etc. The changes made to the procedure will 
prioritize the subject’s safety and data validity and integrity. For any significant change, as per 
regulatory guidelines, a planned protocol deviation will be filled and notified to IRB and/or local 
regulatory (as applicable). 
All participants will be pre-screened prior to enrolment into the study and evaluated for risk factors 
and symptoms of COVID-19 according to the most recent regional Public Health guidelines13 
available at the time of pre-screening. The screening is conducted through telephone at the time 
of appointment confirmation and again when the subject arrives at the clinic for any visit. 
Additional health checks, including body temperature or other vital sign monitoring, etc., may be 
performed during the study at the discretion of the Investigator/designee, even if not specified in 
the protocol. A subject who is tested positive to COVID-19 during the study will be withdrawn from 
the study. This subject and other subjects in close contact will be handled as per applicable local 
Public Health Guidelines. 
As the science and regulations are continuously being adapted to the evolving information around 
the pandemic, additional measures apart from the ones mentioned here may be undertaken to 
ensure subject safety and appropriate study conduct. The IRB would be informed for their review 
and approval as applicable.  
Risk Mitigation plan/Risk Evaluation and Mitigation strategy will be made to minimize the risk for 
COVID-19 exposure and to handle possible situations during the COVID-19 pandemic.  


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20. 
REGULATORY 
 
Institutional Review Board/ Health Canada 
The Investigator agrees to provide the IRB with all appropriate material, including a copy of the 
protocol, consent document, and advertising text (if study-specific advertising is used). The study 
will not be initiated without written IRB approval of the research plan and consent document. The 
Investigator will provide appropriate reports on the progress of this study to the IRB in accordance 
with applicable government and/or Institute regulations. The IRB will be informed of any 
modifications of the protocol or consent document. Approval in writing will be obtained from the 
IRB prior to implementation of any changes which may increase subject risk or which may alter 
the validity or objectives of the data collected. A copy of the IRB approval letter covering such 
alterations will be maintained by the Sponsor (PI). For modifications to the protocol which are 
administrative in nature or do not affect subject risk, the IRB will be notified in writing by the 
Sponsor (PI). 
The Investigator must promptly report to the IRB all unanticipated problems involving risks to 
subjects. This includes AEs and other types of problems (i.e., AEs are a subset of unanticipated 
problems) that the Investigator is required to report to IRB.  
Sponsor should submit a notification to Health Canada indicating that the trial is complete. 
 
Consent Document 
A properly executed, written consent in compliance with current federal codes, GCP, acts and 
regulations and in accordance with ICH Guidance E6 on GCP shall be obtained from each subject 
prior to entering the trial or prior to performing any unusual or non-routine procedure involving risk 
to the subject. The consent document(s) to be used will be reviewed and approved by the Sponsor 
(PI). It will be submitted by the Sponsor (PI) to the IRB for review and written approval prior to the 
start of the study. The Investigator shall provide a copy of the consent to the subject and a signed 
copy shall also be maintained in the study records. Attention is directed to the basic elements 
required in the consent document under current federal regulations for Protection of Human 
Subjects: 
1. A statement verifying the study involves research, an explanation of the purposes 
of the research, the expected duration of the subject's participation, a description 
of the procedures to be followed, and identification of any experimental 
procedures. 
2. A description of any reasonably foreseeable risks or discomforts to the subject.  
3. A description of any benefits to the subject or to others that may reasonably be 
expected from the research. 
4. A disclosure of appropriate alternative procedures or courses of treatment, if any, 
that might be advantageous to the subject. 
5. A statement describing the extent, if any, to which confidentiality of records 
identifying the subject will be maintained and noting the possibility the applicable 
regulatory agencies and the study Sponsor may inspect the records. 


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6. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are 
available if injury occurs and, if so, what they consist of, or where further 
information may be obtained. 
7. An explanation of whom to contact for answers to pertinent questions about the 
research and research subject's rights and whom to contact in the event of a 
research-related injury to the subject. 
8. A statement that participation is voluntary and refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and the subject 
may discontinue participation at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
Additional elements of consent, if appropriate, must be provided to the subject: 
1. A statement that the particular treatment or procedure may involve risks to the 
subject (or to the embryo or fetus, if the subject is or may become pregnant), which 
are currently unforeseeable. 
2. Anticipated circumstances under which the subject's participation may be 
terminated by the Investigator without regard to the subject's consent. 
3. Any additional costs to the subject that may result from participation in the study. 
4. The consequences of a subject's decision to withdraw from the research and 
procedures for orderly termination of participation by the subject. 
5. A statement that significant new findings developed during the course of the 
research that may relate to the subject's willingness to continue participation will 
be provided to the subject. 
6. The approximate number of subjects involved in the study. 
When seeking informed consent for applicable clinical trials, a statement may be provided to the 
subject that clinical trial information has been or will be submitted for inclusion in the clinical trial 
registry databank, if applicable. 
 
Confidentiality 
All information disclosed to the Investigator by the Sponsor or Sponsor designees shall be treated 
by the Investigators as strictly confidential. The Investigator will only use this information for the 
purpose of conducting the clinical trial described within this protocol. The Investigator must agree 
not to disclose any information contained within this protocol to any third party, except to those 
involved in the conduct of this clinical study and who are bound by the obligations of 
confidentiality. 
Information concerning the study treatment, patent applications, processes, unpublished scientific 
data, and other pertinent information is confidential and remains the property of the Sponsor. 
Details should be disclosed only to those involved in the approval or conduct of the study. It is 
understood that the Investigator will use the information obtained during the clinical study in 
connection with the development of the treatment and therefore may disclose it as required to 


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regulatory agencies. The Investigator understands that he has an obligation to provide the 
Sponsor with all data obtained during the study. 
 
Investigator's Statement 
The Investigator agrees to conduct the trial as outlined in the approved protocol and in accordance 
with the 
 guidelines and all applicable federal government codes, acts and regulations, 
GCP requirements and ICH guidance E6 (R2) on Good Clinical Practice. These GCP guidelines 
include, but are not limited to: 
1. Permission to allow the 
 or applicable regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner that 
ensures subject confidentiality. If this study is to be inspected by a regulatory agency, 
Cliantha will be notified as soon as possible. 
2. Submission of the proposed clinical investigation, including the protocol, consent 
document, and advertising text (if study-specific advertising is used) to a duly constituted 
IRB for approval and acquisition of written approval for each, prior to study initiation. 
3. Use of a written consent document obtained prior to entry into the study or prior to the 
performance of any non-routine procedures that involve subject risk. The consent 
document(s) must contain all the elements specified in the federal regulations and have 
been previously approved by 
 and the IRB. 
4. Submission of any proposed change in or deviation from the protocol to the IRB, using 
a signed formal amendment document prepared by 
 and/or Investigator. If the 
change or deviation increases the risk to the study population or adversely affects the 
validity of the clinical investigation or the subject’s rights, IRB approval must be obtained 
prior to implementation. IRB will be notified regarding changes that do not involve risk or 
affect the validity of the investigation or the subject’s rights. 
5. Documentation and explanation of protocol deviations will be made on the appropriate 
case report form page, source document or by written documentation to Cliantha. 
6. The Investigator shall promptly report to the 
 any severe adverse event that may 
reasonably be regarded as caused by, or probably caused by, the study treatments. 
7. The Investigator shall submit timely progress reports to the IRB and Cliantha at 
appropriate intervals, but not to exceed one year. The final report will be submitted to the 
IRB within 4 months after study completion, termination, or discontinuation. 
8. The Investigator and study staff shall maintain accurate source documents from which 
case report form data or source documents are based and accountability records that 
show the receipt and disposition of all test article(s) shipped to the Investigator. 
9. When new information is relevant to participants’ welfare, Investigator must promptly 
inform all participants to whom the information applies that requires to be reported to 
Health Canada as well.  
The Investigator agrees that all information provided by the 
(including pre-clinical data) 
protocols, case reports from data or source documents, and verbal and written information will 


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be kept strictly confidential and confined to the personnel involved in conducting the trial. It is 
recognized this information may be given in confidence to the IRB. 
 
 


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21. REFERENCES  
1. The Definition and Classification of Dry Eye Disease: Report of the Definition and 
Classification Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf. 2007; 
5(2): 75-92. doi:10.1016/s1542-0124(12)70081-2.  
2. Caffery B, Srinivasan S, Reaume CJ, et al. Prevalence of dry eye disease in Ontario, Canada: 
A population-based survey. Ocul Surf. 2019; 17(3): 526-531. doi:10.1016/j.jtos.2019.02.011.  
3. Chan CC, Prokopich CL. Lifitegrast Ophthalmic Solution 5.0% for Treatment of Dry Eye 
Disease: Overview of Clinical Trial Program. J Pharm Pharm Sci. 2019; 22(1): 49-56. doi: 
10.18433/jpps29895. 
4. Phadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on 
Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future 
Challenges. Advances in Pharmaceutics. 2015: 1-12. doi:10.1155/2015/704946 
5. Lin H, Yiu SC. Dry eye disease: A review of diagnostic approaches and treatments. Saudi J 
Ophthalmol. 2014; 28(3): 173-81. doi: 10.1016/j.sjopt.2014.06.002. 
6. 
PrRestasis 
MultiDose™, 
(Cyclosporine 
Ophthalmic 
Emulsion 
0.05% 
w/v), 
Anti-
Inflammatory/Immunomodulator. Allergan Inc, Monograph. June 1 2018. 
7. PrXidra®, Lifitegrast Ophthalmic Solution 5% (w/v), Lymphocyte function associated antigen-
1 (LFA-1) antagonist. Novartis Pharmaceuticals Canada Inc, Monograph. November 21 
2019. 
8. Mandell KJ, Clark D, Chu DS, Foster CS, Sheppard J, Brady TC. Randomized Phase 2 Trial 
of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious 
Anterior Uveitis: Model for Corticosteroid Replacement. J Ocul Pharmacol Ther. 2020; 
36(10): 732-739. doi: 10.1089/jop.2020.0056. 
9. Clark D, Cavanagh B, Shields AL, Karpecki P, Sheppard J, Brady TC. Clinically Relevant 
Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 
ALLEVIATE 
Trial. 
Am 
J 
Ophthalmol. 
2021; 
S0002-9394(21)00222-1. 
doi: 
10.1016/j.ajo.2021.04.023 
10. Clark D, Tauber J, Sheppard J, Brady TC. Early Onset and Broad Activity of Reproxalap in a 
Randomized, Double-Masked, Vehicle-Controlled Phase 2b Trial in Dry Eye Disease. Am J 
Ophthalmol. 202; 226:22-31. doi: 10.1016/j.ajo.2021.01.011 
11. Clark D, Sheppard J, Brady TC. A Randomized Double-Masked Phase 2a Trial to Evaluate 
Activity and Safety of Topical Ocular Reproxalap, a Novel RASP Inhibitor, in Dry Eye Disease. 
J Ocul Pharmacol Ther. 2021; 37(4): 193-199. doi: 10.1089/jop.2020.0087 
12. Reproxalap (ADX-102) Topical Ophthalmic Solution Investigator’s Brochure, Edition 7.0, 
Dated 12 Feb 2021. 
13. COVID-19 for health professionals. Peel Region. https://www.peelregion.ca/health-
professionals/covid-19/. Accessed May 23, 2021.