Clinical trial NCT05992922
Conditions: Dry Eye Syndromes
Sponsor: Iacta Pharmaceuticals
Start date: 2023-10-17; Completion date: 2023-12-19
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability and efficacy of IC265 compared to vehicle in participants with signs and symptoms dry eye disease.

Detailed description:

Arms: arm 1: 1 drop will be instilled in each eye twice daily. arm 2: 1 drop will be instilled in each eye twice daily.
Interventions: intervention 1: IC265 Ophthalmic Solution 1% intervention 2: Placebo Ophthalmic Solution (Vehicle)
Intervention descriptions: intervention 1: 1 drop will be instilled in each eye twice a day intervention 2: 1 drop will be instilled in each eye twice a day

Protocol documents:
Prot_000.pdf: 
IACTA Pharmaceuticals, Inc. 
 
Protocol IC265-0001 
IC265 Ophthalmic Solution 
 
IND 130141 
 
 
NCT 05992922   
12 June 2023 
A Phase 2, Single-Center, Randomized, Double-Masked, Placebo-
Controlled Study to Assess the Safety and Efficacy of IC265 Ophthalmic 
Solution 1% in Subjects Diagnosed with Dry Eye Disease 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol 
IC265 Ophthalmic Solution 
 
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Clinical Trial Protocol 
Protocol Title: 
A Phase 2, Single-Center, Randomized, Double-
Masked, Placebo-Controlled Study to Assess the 
Safety and Efficacy of IC265 Ophthalmic Solution 
1% in Subjects Diagnosed with Dry Eye Disease 
Protocol Number: 
23-110-0002 
Study Phase: 
2 
Investigational Product Name: 
IC265 Ophthalmic Solution 
IND Number: 
130141 
Indication: 
Dry Eye Disease 
Investigators: 
Single-Center 
Sponsor: 
IACTA Pharmaceuticals, Inc 
19900 MacArthur Blvd, Suite 550 
Irvine, CA 92612 
 
Contract Research 
Organization: 
Ora. Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 USA 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
949-542-3882 www.alphairb.com 
Version 
1.0 
Original Protocol (Version 1.0): 12 Jun 2023 
 
 
Confidentiality Statement 
 
This protocol contains confidential, proprietary information of Ora, Inc. and/or IACTA 
Pharmaceuticals, Inc. Further dissemination, distribution or copying of this protocol or its 
contents is strictly prohibited. 
 


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SPONSOR PERSONNEL 
Chief Medical Officer: 
Eric Carter 
Tel: (949) 466-5928 
Fax: N/A 
Email: ec@iactapharma.com 
Medical Monitor: 
Anoshie Ratnayake 
Tel: (949) 629-8686 
Fax: N/A 
Email: ar@iactapharma.com 
ORA PERSONNEL 
Department Senior Vice 
President: 
George Ousler 
Tel: (978) 685-8900 x 1089 
Fax: (978) 689-0020 
gousler@oraclinical.com 
Department Director: 
Juli Chalifour 
Tel: (978) 685-8900 x 1045 
Fax: (978) 849-7371 
jchalifour@oraclinical.com 
Clinical Project Manager: 
David Welch 
Tel: (978) 685-8900 x 1349 
Fax: (978) 689-0020 
dawelch@oraclinical.com 
 
MEDICAL MONITOR 
Medical Monitor: 
Joseph B. Ciolino 
Tel: (617) 573-5575 
Cell: (401) 935-9662 
Fax: (617) 573-4324 
Joseph_ciolino@meei.harvard.edu 
 
 


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SYNOPSIS 
Protocol Title: 
A Phase 2, Single-Center, Randomized, Double-Masked, Placebo-Controlled Study 
to Assess the Safety and Efficacy of IC265 Ophthalmic Solution 1% in Subjects with 
Dry Eye Disease 
Protocol Number: 
23-110-0002 
Investigational 
Product: 
1. IC265 Ophthalmic Solution 1% 
2. Placebo Ophthalmic Solution 
Study Phase: 
2 
Objective(s): 
The objective of this study is to compare the safety and efficacy of IC265 
Ophthalmic Solution 1% to placebo for the treatment of the signs and symptoms of 
dry eye disease. 
Overall Study Design: 
Structure: 
Single-center, randomized, double-masked, placebo-controlled 
Duration: 
An individual subject’s participation is estimated to be approximately 14 weeks (84 
days) 
Controls: 
Placebo (vehicle minus active) Ophthalmic Solution 
Dosage/Dose 
Regimen/ 
Instillation/Applic
ation/Use: 
Subjects eligible to be randomized will receive one of the following treatments to be 
administered bilaterally BID for 84 days (from Visit 2 to Visit 5). 
1) IC265 Ophthalmic Solution 1% 
2) Placebo Ophthalmic Solution (Vehicle) 
During a 14 -day study run-in period (for the purpose of subject selection) prior to 
randomization, all subjects will receive Placebo Ophthalmic Solution (Vehicle) 
bilaterally BID. 
Summary of Visit 
Schedule: 
5 visits over the course of approximately 14 weeks 
• 
Visit 1 = Day -14 ± 2, Screening (CAE® visit) 
• 
Visit 2 = Day 1, CAE Confirmation/Baseline (CAE® visit) 
• 
Day 8, Safety Phone Follow Up 
• 
Visit 3 = Day 15 ± 2, 2-Week Follow Up (CAE® visit) 
• 
Day 29, Safety Phone Follow Up 
• 
Visit 4 = Day 43 ± 2, 6-Week Follow Up (CAE® visit) 
• 
Day 64, Safety Phone Follow Up 
• 
Visit 5 = Day 85 ± 4, 12-Week Follow-Up/Study Exit (CAE® visit) 
Measures Taken 
to Reduce Bias: 
This is a randomized treatment assignment, double-masked study 
Study Population Characteristics: 
Number of 
Subjects: 
Approximately 80 subjects will be screened to enroll 40 subjects (20 randomized 
subjects in each treatment group) 
Condition/Disease
: 
Dry Eye Disease 
Inclusion Criteria: 
Subjects must: 
1. Be at least 18 years of age; 
2. Provide written informed consent; 
3. Have a reported or documented history of dry eye for at least 6 months prior to Visit 1; 
4. Have a history of use or desire to use eye drops for dry eye symptoms within 6 months of Visit 1; 
5. Report a score of ≥ 2 on the Ora Calibra Ocular Discomfort & 4-symptom questionnaire in at least one 
symptom at Visits 1 and 2; 
6. Have a Schirmer’s Test score of ≤ 10 mm and ≥ 1 mm in at least one eye at Visits 1 and 2; 
7. Have a pre-CAE conjunctival redness score ≥ 1 according to the Ora Calibra Conjunctival Redness for 
Dry Eye Scale in at least one eye at Visits 1 and 2; 
8. Have a corneal fluorescein staining score of ≥ 2 in at least one region (e.g. inferior, superior, or central) 
at Visits 1 and 2; 
9. Have a sum corneal fluorescein staining score of ≥ 4, based on the sum of the inferior, superior, and 
central regions, at Visits 1 and 2;  
10. Have a total lissamine green conjunctival score of ≥ 2, based on the sum of the temporal and nasal 
regions at Visits 1 and 2; 
11. Demonstrate a response to the CAE at Visits 1 and 2 as defined by: 


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a. Having at least a ≥1 point increase in fluorescein staining in the inferior region in at least one eye 
following CAE exposure 
b. Reporting an Ora Calibra Ocular Discomfort Score ≥3 at 2 or more consecutive time points in at 
least one eye during CAE exposure (if a subject has an ocular discomfort rating of 3 at time = 0 
for an eye, s/he must report an ocular discomfort rating of 4 for two consecutive measurements for 
that eye) Note: a subject cannot have an ocular discomfort score of 4 at time = 0); 
12. Have at least one single eye satisfy all criteria for for 6, 7, 8, 9, 10, and 11 above. 
Exclusion Criteria: 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Have any clinically significant slit lamp findings at Visit 1 that may include active blepharitis, 
meibomian gland dysfunction, ocular rosacea, lid margin inflammation, or active ocular 
allergies that require therapeutic treatment; 
2. Have any clinically significant (CS) posterior chamber findings, or a history of such 
findings/disorders, that may include exudative (i.e., wet) age-related macular degeneration, 
retinal vein occlusion, diabetic retinopathy, glaucoma, ocular hypertension, or any other retinal 
or optic nerve disease/disorder that require therapeutic treatment and/or in the opinion of the 
Investigator may interfere with study parameters; 
3. Have worn contact lenses within 48 hours prior to Visit 1 or anticipate using contact lenses 
during the study; 
4. Have laser-assisted in situ keratomileusis (LASIK) or similar type of corneal refractive surgery 
and/or any other ocular surgical procedure within 12 months prior to Visit 1; or have any ocular 
surgical procedure scheduled to be conducted during the study period; 
5. Have had any surgeries of the ocular surface or lid in the past 6 months; 
6. Have a history of lacrimal duct obstruction in either eye within 12 months prior to Visit 1; 
7. Have used temporary (i.e., collagen) punctal plugs within 12 weeks prior to Visit 1 or anticipate 
their use during the study period; 
8. Have permanent punctal plugs inserted or removed – including falling out – or have had surgical 
punctal occlusion within 12 weeks prior to Visit 1 or anticipate any such event at any time 
during the study period; 
9. Use any of the following treatments in the period indicated before Visit 1 or anticipate their use 
at any time during the study. 
24 hours prior to Visit 1 
10. All topical ophthalmic preparations (e.g., medications for glaucoma, over-the counter-solutions, 
artificial tears, gels, scrubs, ointments) 
72 hours prior to Visit 1 
11. Antihistamines (including topical ophthalmic and nasal antihistamines) 
30 days prior to Visit 1 
12. Topical ophthalmic non-steroidal anti-inflammatories 
13. Topical ophthalmic corticosteroids 
14. Topical ophthalmic autologous serum 
15. Topical ophthalmic antibiotics 
16. Mast cell stabilizers 
17. Oral aspirin or aspirin-containing products except in the case that it was taken on a stable dosing 
regimen for at least 30 days prior to Visit 1 and is expected to be taken on the same regimen 
throughout the study period 
18. Any other medication known to cause ocular drying (e.g., antidepressants, beta blockers) except 
in the case that it was taken on a stable dosing regimen for at least 30 days prior to Visit 1 and is 
expected to be taken on the same regimen throughout the study period 
19. Restasis® 
20. Xiidra® 
21. CEQUA™ 
22. LipiFlow® or other similar meibomian gland dysfunction (MGD) therapy 
23. TrueTear® 
24. Corticosteroids (e.g., systemic steroids including intravenous, intramuscular, intraarticular, and 
oral steroids; nasal steroids; facial topical steroids; dermatological steroids with high potency or 
large treatment areas); 
25. Tetracyclines (tetracycline, doxycycline, minocycline, etc.); 
26. Be monocular or have best corrected visual acuity greater than or equal to logMAR +0.7 in 
either eye as assessed by the ETDRS scale at Visit 1; 


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27. Have a severe systemic disease, chronic illness or uncontrolled medical condition including, but 
not limited to, severe cardiopulmonary disease, poorly controlled hypertension, poorly 
controlled diabetes and/or clinically significant (CS) hematologic, renal or liver disease that in 
the opinion of the Investigator could interfere with study assessments or limit compliance; 
28. Be a woman who is pregnant, nursing or planning a pregnancy; 
29. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 5 (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, bilateral tubal ligation, or bilateral oophorectomy), or is 
post-menopausal (i.e., without menses for 12 consecutive months); 
30. Be a woman of childbearing potential who is not using an acceptable means of birth control. 
Acceptable methods of contraception include hormonal (e.g., oral, implantable, injectable, or 
transdermal contraceptives), mechanical (e.g., 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 females, abstinence might be regarded as an adequate method of birth control; 
however, if the subject became sexually active during the study, she must agree to use adequate 
birth control as defined above for the remainder of the study; 
31. Have a known hypersensitivity or contraindication to the investigational products (IPs) or their 
components; 
32. 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 (e.g., any planned procedure or surgery during the study period); 
33. Be currently enrolled in an investigational drug or device study or have used an investigational 
drug or device within 30 days prior to Visit 1; 
34. Have previously participated in a clinical trial with IC265 (previously called PRT-2761); 
35. Be, in the opinion of the Investigator, unable or unwilling to comply with the study protocol, 
including participation in all study assessments, visits, and dosing, or be unable to instill eye 
drops successfully. Subject non-compliance with dosing during the run-in period, defined as < 
80% or > 125% of expected doses taken, might be exclusionary if, in the opinion of the 
Investigator, the subject is likely to be non-compliant with subsequent dosing regimens or other 
study assessments; or 
36. Be an employee of the site that is directly involved in the management, administration, or 
support of this study or be an immediate family member of the same. 
Evaluation Criteria: 
Efficacy Measures 
and Endpoints: 
Efficacy Measures: 
The following endpoints will be tested in the study eye: 
• 
Fluorescein staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, 
and pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) 
in the following regions: central, superior, inferior, temporal, nasal, corneal 
sum, conjunctival sum, and total eye score 
• 
Ocular discomfort and dry eye symptoms at Visits 3, 4 (pre-CAE, post-
CAE, and pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-
CAE)  
• 
Lissamine green staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-
CAE, and pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-
CAE) in the following regions: central, superior, inferior, temporal, nasal, 
corneal sum, conjunctival sum, and total eye score 
• 
Tear film break-up time at Visits 3, 4 (pre-CAE, post-CAE, and pre- to 
post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) 
• 
Conjunctival Redness at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-
CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE), and mean change 
from baseline Visit 2 (Day 1) pre-CAE to Visit 5 (Day 84) pre-CAE 
• 
Ocular Surface Disease Index (OSDI) at Visits 3, 4, and 5 (pre-CAE) 
• 
Schirmer’s test at Visit 3, 4, and 5 
• 
Ocular discomfort during CAE at Visits 4 and 5 
• 
Daily Diary Symptom Score  
Safety/Tolerability 
Measures: 
• 
Visual acuity 
• 
Slit-lamp evaluation 
• 
Adverse event query 
• 
Intraocular pressure 


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• 
Undilated fundoscopy 
• 
Drop comfort assessment after randomization at Visit 2, 3, 4, and 5 
General Statistical Methods and Types of Analyses 
Analysis Populations 
• 
Intent-to-Treat Population – The intent-to-treat (ITT) population includes all randomized subjects. 
Efficacy analyses will be performed on the ITT population with observed data only. The ITT 
population may also be analyzed using the Last Observation Carried Forward (LOCF) imputation 
method and multiple imputation to assess sensitivity. 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. The PP population will be analyzed using 
observed data only for efficacy variables. 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. The safety population will be analyzed for all safety 
assessments. Subjects in the Safety population will be analyzed as treated.  
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: 
Study 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 study eye will be the eye with the worst (higher) total corneal fluorescein 
staining, based on the sum of the inferior, superior, and central regions, at baseline (Visit 2) pre-CAE. If the 
total corneal staining is the same in both eyes, then the right eye will be selected as the study eye. 
Sample Size 
Approximately 80 subjects will be screened to enroll 40 subjects (20 subjects in each group). This is a 
Phase 2 study for which no formal sample size calculation has been performed. The sample size chosen was 
not based on statistical considerations, but is based on historical experience. 
Multiplicity Considerations 
As this is an exploratory study with no primary or secondary endpoints, there will be no multiplicity 
adjustments and all analyses are considered hypothesis-generating.  
Efficacy Endpoints Analysis 
The method of analysis for efficacy endpoints will be based on the distribution of the individual variable for 
analysis. Variables recorded on a continuous scale will be analyzed at each visit using two-sample t-tests 
and Wilcoxon rank sum tests. Each visit and treatment group will be summarized using descriptive statistics 
for the ITT population with observed data only. Changes from baseline will be summarized by visit and 
treatment using descriptive statistics and analyzed by visit using ANCOVA models with baseline value and 
treatment group, two sample t-tests and Wilcoxon rank sum tests on the ITT population with observed data 
only. 
For multinomial outcome variables, a generalized linear model will be used, and the distribution will be 
specified as multinomial. 
The ITT population will be analyzed using LOCF imputation for the primary efficacy analysis. For 
sensitivity analyses on the primary and key secondary endpoints, observed data will be used on the ITT and 
PP population, and multiple imputation will be used on the ITT population. Further details will be included 
in the statistical analysis plan (SAP). Analyses using ANCOVA or generalized linear models including data 
from both regions will include a fixed effect of region. 
 
Safety Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Frequencies and percentages will be provided per treatment group of subjects with treatment-
emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An adverse event is treatment emergent if it occurs or worsens after the first 
dose of randomized study treatment. Furthermore, frequencies will be given of subjects with TEAEs by 
system organ class and preferred term, by system organ class, preferred term and maximal severity, by 
system organ class, preferred term for treatment-related adverse events (AEs), by system organ class and 
preferred term for serious adverse events (SAEs); and by system organ class, preferred term, and day of 
onset. Separate analyses will be performed for ocular and non-ocular adverse events. 
The incidence of patients who experience a TEAE of interest over the 12-week post-treatment observation 
period will be compared between the IC265 and placebo groups. A generalized linear model will be used. 


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The incidence of patients who experience a composite of one or more MedDRA preferred terms of interest 
over the 12-week post-treatment observation period will be compared between the IC265 and placebo 
groups. A generalized linear model will be used, and the distribution will be specified as binomial. 
Other safety endpoints will be summarized by treatment and visit using descriptive statistics. Change or 
shift from baseline will also be summarized where appropriate. For assessments performed by eye, both 
eyes will be summarized separately. 
 
 


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TABLE OF CONTENTS 
Synopsis ......................................................................................................................4 
Table of Contents ........................................................................................................9 
List of Abbreviations .........................................................................................................12 
1.0 Introduction ...............................................................................................................13 
2.0 Study Objectives .......................................................................................................14 
3.0 Clinical Hypothesis ...................................................................................................14 
4.0 Overall Study Design ................................................................................................14 
5.0 Study Population .......................................................................................................16 
5.1 
Number of Subjects (approximate) ................................................................16 
5.2 
Study Population Characteristics ....................................................................16 
5.3 
Inclusion Criteria ............................................................................................16 
5.4 
Exclusion Criteria ...........................................................................................17 
5.5 
Withdrawal Criteria (if applicable) ................................................................19 
6.0 Study Parameters ......................................................................................................19 
6.1 
Efficacy Endpoints .........................................................................................19 
6.2 
Safety Measures .............................................................................................20 
7.0 Study materials..........................................................................................................20 
7.1 
Study Treatments ............................................................................................20 
7.1.1 
Study Drug Formulation ...................................................................20 
7.1.2 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period. ...........................21 
7.1.3 
Instructions for Use and Administration ...........................................21 
7.2 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ...................................................................................21 
7.2.1 
Labeling/Packaging...........................................................................21 
7.2.2 
Storage of Investigational Product ....................................................21 
7.2.3 
Accountability of Investigational Product ........................................21 
7.2.4 
Return or Disposal of Investigational Product ..................................21 
7.3 
Other Study Supplies ......................................................................................21 
8.0 Study Methods and Procedures .................................................................................22 
8.1 
Subject Entry Procedures ...............................................................................22 
8.1.1 
Overview ...........................................................................................22 
8.1.2 
Informed Consent..............................................................................22 
8.1.3 
Washout Intervals .............................................................................22 
8.1.4 
Procedures for Final Study Entry ......................................................22 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................22 
8.2 
Concurrent Therapies .....................................................................................22 
8.2.1 
Prohibited Medications/Treatments ..................................................22 
8.2.2 
Escape Medications ..........................................................................22 
8.2.3 
Special Diet or Activities ..................................................................22 
8.3 
Examination Procedures .................................................................................23 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objectives ...............................................................................23 
8.3.2 
Visit 1: Day –14 ± 2 – CAE Screening .............................................23 
8.3.3 
Visit 2: Day 1 – CAE® Confirmation and Baseline ..........................24 
8.3.4 
Safety Phone Follow-Up: Day 8, Day 29, and Day 64 .....................25 
8.3.5 
Visit 3: Day 15 ± 2 ............................................................................25 
8.3.6 
Visit 4: Day 43 ± 2 ............................................................................26 


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8.3.7 
Visit 5: Day 85 ± 4 ............................................................................27 
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 ..............................................................................29 
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 ................................................................30 
9.0 Adverse Events .........................................................................................................30 
9.1 
Adverse Event (AE) .......................................................................................30 
9.1.1 
Severity .............................................................................................30 
9.1.2 
Relationship to Investigational Product ............................................31 
9.1.3 
Expectedness .....................................................................................30 
9.2 
Serious Adverse Events ..................................................................................31 
9.3 
Procedures for Reporting Serious Adverse Events ........................................32 
9.3.1 
Reporting a Serious Unexpected Suspected Adverse Reaction ........32 
9.3.2 
Reporting a Serious Adverse Event ..................................................33 
9.4 
Procedures for Unmasking (if applicable) ......................................................33 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ........34 
10.0 Statistical Hypotheses and Methods of Analysis ......................................................34 
10.1 Analysis Populations ......................................................................................34 
10.2 Statistical Hypotheses .....................................................................................34 
10.3 Sample Size ....................................................................................................35 
10.4 Statistical Analysis .........................................................................................35 
10.4.1 General Considerations .....................................................................35 
10.4.2 Unit of Analysis ................................................................................35 
10.4.3 Missing Data .....................................................................................36 
10.4.4 Multiplicity Consideration ................................................................36 
10.4.5 Efficacy Analyses .............................................................................36 
10.4.6 Safety Variables ................................................................................36 
10.4.7 Interim Analyses ...............................................................................37 
11.0 Compliance with Good Clinical Practices, Ethical Considerations, and Administrative 
Issues .........................................................................................................................37 
11.1 Protection of Human Subjects ........................................................................37 
11.1.1 Subject Informed Consent.................................................................37 
11.1.2 Institutional Review Board (IRB) Approval .....................................37 
11.2 Ethical Conduct of the Study ..........................................................................37 
11.3 Subject Confidentiality ...................................................................................37 
11.4 Documentation ...............................................................................................38 
11.4.1 Retention of Documentation .............................................................38 
11.5 Recording of Data on Source Documents and Case Reports Forms (CRFs) .38 
11.6 Publications ....................................................................................................39 
12.0 References .................................................................................................................40 
13.0 Appendices ................................................................................................................41 
13.1 Appendix 1: Schedule Of Visits And Measurements .....................................41 
13.2 Appendix 2: Examination Procedures, Tests, & Evaluations ........................43 
13.3 Appendix 3: Protocol Amendment Summary ................................................52 


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13.4 Appendix 4: Sponsor And Ora Approvals .....................................................53 
13.5 Appendix 5: Investigator’s Signature .............................................................54 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BID 
Twice Daily 
CAE 
Controlled Adverse Environment 
CDs 
Compact Discs 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DED 
Dry Eye Disease 
eCRF 
electronic Case Report Form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
IWRS 
Interactive Web Response System 
LASIK 
Laser In Situ Keratomileusis 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
OCT 
Optical Coherent Tomography 
OSDI 
Ocular Surface Disease Index 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
TFBUT 
Tear Film Break-Up time 
TEAEs 
Treatment-Emergent Adverse Events 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 
 


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1.0 
INTRODUCTION 
Dry eye disease (DED) is a prevalent chronic eye condition affecting between 5% and 34% 
of the population worldwide, and approximately 1 million to 4 million Americans between 65 
to 84 years of age (Fiscella 2011, Messmer 2015). This multifactorial disease has 
considerable socio-economic implications, including daily activities, visual function, social 
and physical functioning, workplace productivity, and quality of life (Pflugfelder 2008). 
According to the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) 
II, “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of 
homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film 
instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory 
abnormalities play etiological roles” (Craig, Nichols et al. 2017). Recurrent corneal erosion 
and ocular surface inflammation are often painful and cause visual function impairment, 
significantly reducing the quality of life of patients. 
Treatment approaches vary but generally employ the use of artificial tears to combat dryness 
or target the inflammatory aspect of the disease. While artificial tears often relieve some of 
the symptoms in the short term, many doses are required throughout the day and the 
underlying cause is left untreated. The Food and Drug Administration (FDA)-approved 
treatments that focus on inflammation for dry eye disease are 0.05% cyclosporine-A 
ophthalmic emulsion (Restasis®, Allergan), 0.09% cyclosporine ophthalmic solution 
(CEQUATM, Sun Pharmaceutical Industries, Inc), and lifitegrast 5% ophthalmic solution 
(Xiidra®, Shire US, Inc.). 
To target the inflammatory aspect of DED, IACTA Pharmaceuticals, Inc. is currently 
developing IC265 ophthalmic solution with drug substance previously known as PRT-2761, a 
potent inhibitor of Syk. PRT-2761 is a small molecule in the pyrimidine carboxamide class 
that functions as a specific inhibitor to spleen tyrosine kinase (Syk). Syk is a non-receptor 
protein tyrosine kinase critical for B-cell activation and development and for signaling 
through the activating class of Fc receptors that are expressed on a wide range of 
hematopoietic cells including mast cells, macrophages, and neutrophils. Upon Fc receptor 
ligation, Syk binds to the di-phosphorylated immunomodulatory tyrosine-based activation 
motif (ITAM) harboring adaptor protein FcRγ, resulting in tyrosine phosphorylation of 
multiple downstream substrates that ultimately regulates cell survival, functional activation, 
differentiation, and clonal expansion (Ulanova, Duta et al. 2005). Syk is critical to the 
regulation of immune cell activation in response to ligation of a variety of receptors, making 
it an intriguing target for the treatment of inflammatory and autoimmune disorders. Inhibitors 
of Syk are currently in development for a number of diseases including heparin-induced 
thrombocytopenia, idiopathic thrombocytopenia, and chronic lymphocytic leukemia (Reilly, 
Sinha et al. 2011, Hoellenriegel, Coffey et al. 2012, Markham 2018).  
The non-clinical program for PRT-2761 (drug substance of IC265 ophthalmic solution) 
consisted of: proof-of concept studies in a murine conjunctival allergen challenge (CAC) 
model, non-Good Laboratory Practice (GLP) pharmacokinetic studies in rats and rabbits, 28 
days GLP oral toxicity and toxicokinetic studies in rats, and 28 days GLP ocular toxicity and 
toxicokinetic studies in Dutch Belted rabbits and beagle dogs. No clinical studies for the 
treatment of DED have been conducted with PRT-2761. However, clinical experience and 
safety with PRT-2761 has been demonstrated for the treatment of acute and chronic allergic 
conjunctivitis in a single-center phase 2 study.  


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2.0 
STUDY OBJECTIVES 
The objective of this study is to compare the safety and efficacy of IC265 Ophthalmic 
Solution 1% to placebo for the treatment of the signs and symptoms of dry eye disease. 
3.0 
CLINICAL HYPOTHESIS 
The clinical hypotheses for this study is that IC265 Ophthalmic Solution 1% twice daily 
(BID) is superior to its vehicle (BID) for the following endpoints of signs and symptoms of 
dry eye, as follows:  
• Fluorescein staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, and pre- 
to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the following 
regions: central, superior, inferior, temporal, nasal, corneal sum, conjunctival sum, 
and total eye score 
• Ocular discomfort and dry eye symptoms at Visits 3, 4 (pre-CAE, post-CAE, and pre- 
to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) 
• Lissamine green staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, and 
pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the 
following regions: central, superior, inferior, temporal, nasal, corneal sum, 
conjunctival sum, and total eye score 
• Tear film break-up time at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), 
and 5 (pre-CAE, post-CAE, and pre- to post-CAE) 
• Conjunctival Redness at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 
5 (pre-CAE, post-CAE, and pre- to post-CAE), and mean change from baseline Visit 
2 (Day 1) pre-CAE to Visit 5 (Day 85) pre-CAE 
• Ocular Surface Disease Index (OSDI) at Visits 3, 4, and 5 
• Schirmer’s test at Visit 3, 4, and 5 
• Ocular discomfort during CAE at Visits 4 and 5 
• Daily diary symptom score  
4.0 
OVERALL STUDY DESIGN 
This is a Phase 2, single-center, double-masked, randomized, placebo-controlled clinical 
study. Subjects will be randomized to one of the following treatment arms at Visit 2 (Day 1):  
• IC265 Ophthalmic Solution 1%: 1 drop BID bilaterally (N=~20) 
• Placebo Ophthalmic Solution (Vehicle): 1 drop BID bilaterally (N=~20) 
Approximately 40 subjects will be randomly assigned to one of the two groups (1:1) to 
receive either IC265 Ophthalmic Solution 1% or placebo solution as topical ophthalmic drops 
administered bilaterally BID for 12 weeks. Subjects, Sponsor, Contract Research 
Organization (CRO), and site personnel will be masked to treatment assignment. 
During the 14-day study run-in period prior to randomization, all subjects will receive 
Placebo Ophthalmic Solution (Vehicle) bilaterally BID.  
During the screening period, two 90-minute exposures to the CAE will be conducted to 
ascertain eligibility to enter the study at Visit 1 (Day -14 ± 2) and Visit 2 (Day 1). Subjects 
who qualify after the initial screening visit will enter the run-in phase, where they will self-
administer vehicle BID for approximately 14 days. Those who qualify at Visit 2 (Day 1) will 
be randomized to receive study drug in a double-masked fashion for 84 days. Subjects will 


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self-administer drops BID and will complete Daily diary symptom score assessments as 
instructed. 
The CAE exposure will occur at Visit 1 (Day -14 ± 2), Visit 2 (Day 1), Visit 3 (Day 15 ± 2), 
Visit 4 (Day 43 ± 2), and Visit 5 (Day 85 ± 4), with Pre-CAE, during CAE and Post-CAE 
assessments of ocular signs and symptoms. Study drug will be discontinued at Visit 5. 
Subjects will exit from the study at this visit.  
A study design flow chart is provided below: 
Visit 1 
(Day -14 ± 2 day): 
CAE Screening 
Informed Consent/HIPAA 
Medical History and Demographic 
Urine Pregnancy Testing (as needed) 
Pre-CAE Eye Evaluation / Review of Qualification Criteria 
CAE Exposure  
Post-CAE Eye Evaluation / Review of Qualification Criteria 
Sign and Symptom Efficacy Assessment Pre-CAE and Post-CAE  
Safety Assessments (Visual Acuity, Slit-lamp biomicroscopy, Intraocular 
Pressure [IOP], Undilated Fundoscopy, Adverse Event [AE] Query) 
Placebo Run-In Dispensation 
Daily Diary Dispensation 
 
 
Placebo Run-in Period (~14 days) 
 
 
Visit 2 
(Day 1): 
CAE Confirmation/Baseline 
Collection of Placebo Run-in 
Collection of Daily Diary Symptom Score 
Update Medical / Medication History 
Physical Exam (HEENT) 
Pre-CAE Eye Evaluation / Review of Qualification Criteria 
CAE Exposure  
Post-CAE Eye Evaluation / Review of Qualification Criteria 
Sign and Symptom Assessment Pre-CAE and Post-CAE 
Safety Assessments (Slit-lamp biomicroscopy, AE Query) 
Randomization and Treatment Kit Dispensation 
In-Office Randomized Treatment Dose 
Daily Diary Dispensation 
Drop Comfort Scale Assessments  
 
 
Day 8: Safety Phone Follow-Up 
AE Query 
 
 
Visit 3 
(Day 15 ± 2): 
2-Week CAE Follow-Up 
Collection of Daily Diary Symptom Score 
Medical / Medication History Update 
Pre-CAE Eye Evaluation  
CAE Exposure  
Post-CAE Eye Evaluation  
Sign and Symptom Assessment Pre-CAE and Post-CAE 
Safety Assessments (Slit-lamp biomicroscopy, AE Query) 
In-Office Randomized Treatment Dose 
Daily Diary Dispensation 
Drop Comfort Scale Assessments 
 
 
Day 29: Safety Phone Follow-Up 
AE Query 


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Visit 4 
(Day 43 ± 2): 
6-Week CAE Follow Up 
Collection of Daily Diary Symptom Score 
Update Medical / Medication History 
Pre-CAE Eye Evaluation  
CAE Exposure  
Post-CAE Eye Evaluation  
Sign and Symptom Assessment Pre-CAE and Post-CAE 
Safety Assessments (Slit-lamp biomicroscopy, AE Query) 
Treatment Kit Dispensation 
In-Office Randomized Treatment Dose 
Daily Diary Dispensation 
Drop Comfort Scale Assessments 
 
 
Day 64: Safety Phone Follow-Up 
AE Query 
 
Visit 5 
(Day 85 ± 4)/Early Termination: 
12-Week CAE Follow Up and 
Study Exit 
Collection of Daily Diary Symptom Score 
Update Medical / Medication History 
Pre-CAE Eye Evaluation 
CAE Exposure  
Post-CAE Eye Evaluation 
Sign and Symptom Assessment Pre-CAE and Post-CAE 
Safety Assessments (Slit-lamp biomicroscopy, IOP, Undilated Fundoscopy, 
AE Query) 
Study Exit  
5.0 
STUDY POPULATION 
5.1 
NUMBER OF SUBJECTS (APPROXIMATE) 
Approximately 80 subjects will be screened to enroll 40 subjects (20 in each group). Subjects 
will be randomized in each treatment arm. Subjects will be randomized in a 1:1 ratio of  
• IC265 Ophthalmic Solution 1% 
• Placebo Ophthalmic Solution (Vehicle) 
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 
Each subject must: 
1. Be at least 18 years of age; 
2. Provide written informed consent; 
3. Have a reported or documented history of dry eye for at least 6 months prior to Visit 1; 
4. Have a history of use or desire to use eye drops for dry eye symptoms within 6 months of 
Visit 1, except as noted below in Section 5.4(Error! Reference source not found.); 
5. Report a score of ≥ 2 on the Ora Calibra® Ocular Discomfort & 4-symptom questionnaire 
in at least one symptom at Visits 1 and 2; 


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6. Have a Schirmer’s Test score of ≤ 10 mm and ≥ 1 mm in at least one eye at Visits 1 and 
2; 
7. Have a pre-CAE conjunctival redness score ≥ 1 according to the Ora Calibra® 
Conjunctival Redness for Dry Eye Scale in at least one eye at Visits 1 and 2; 
8. Have a corneal fluorescein staining score of ≥ 2 in at least one region (e.g. inferior, 
superior, or central) at Visits 1 and 2; 
9. Have a sum corneal fluorescein staining score of ≥ 4, based on the sum of the inferior, 
superior, and central regions, at Visits 1 and 2;  
10. Have a total lissamine green conjunctival score of ≥ 2, based on the sum of the temporal 
and nasal regions at Visits 1 and 2; 
11. Demonstrate a response to the CAE® at Visits 1 and 2 as defined by: 
a. Having at least a ≥1 point increase in fluorescein staining in the inferior region in at 
least one eye following CAE® exposure 
b. Reporting an Ora Calibra® Ocular Discomfort Score ≥3 at 2 or more consecutive time 
points in at least one eye during CAE® exposure (if a subject has an ocular discomfort 
rating of 3 at time = 0 for an eye, s/he must report an ocular discomfort rating of 4 for 
two consecutive measurements for that eye) Note: a subject cannot have an ocular 
discomfort score of 4 at time = 0); 
12. Have at least one single eye satisfy all criteria for 6, 7, 8, 9, 10, and 11 above. 
5.4 
EXCLUSION CRITERIA 
Each subject may not: 
1. Have any clinically significant slit lamp findings at Visit 1 that may include active 
blepharitis, meibomian gland dysfunction, ocular rosacea, lid margin inflammation, or 
active ocular allergies that require therapeutic treatment; 
2. Have any clinically significant (CS) posterior chamber findings, or a history of such 
findings/disorders, that may include exudative (i.e., wet) age-related macular 
degeneration, retinal vein occlusion, diabetic retinopathy, glaucoma, ocular hypertension, 
or any other retinal or optic nerve disease/disorder that require therapeutic treatment 
and/or in the opinion of the Investigator may interfere with study parameters; 
3. Have worn contact lenses within 48 hours prior to Visit 1 or anticipate using contact 
lenses during the study; 
4. Have laser-assisted in situ keratomileusis (LASIK) or similar type of corneal refractive 
surgery and/or any other ocular surgical procedure within 12 months prior to Visit 1; or 
have any ocular surgical procedure scheduled to be conducted during the study period; 
5. Have had any surgeries of the ocular surface or lid in the past 6 months;  
6. Have a history of lacrimal duct obstruction in either eye within 12 months prior to Visit 
1; 
7. Have used temporary (i.e., collagen) punctal plugs within 12 weeks prior to Visit 1 or 
anticipate their use during the study period; 
8. Have permanent punctal plugs inserted or removed – including falling out – or have had 
surgical punctal occlusion within 12 weeks prior to Visit 1 or anticipate any such event at 
any time during the study period; 


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9. Use any of the following treatments in the period indicated before Visit 1 or anticipate 
their use at any time during the study. 
24 hours prior to Visit 1 
a. All topical ophthalmic preparations (e.g., medications for glaucoma, over-the 
counter-solutions, artificial tears, gels, scrubs, ointments) 
72 hours prior to Visit 1 
b. Antihistamines (including topical ophthalmic and nasal antihistamines) 
30 days prior to Visit 1 
c. Topical ophthalmic non-steroidal anti-inflammatories 
d. Topical ophthalmic corticosteroids  
e. Topical ophthalmic autologous serum 
f. Topical ophthalmic antibiotics 
g. Mast cell stabilizers 
h. Oral aspirin or aspirin-containing products except in the case that it was taken 
on a stable dosing regimen for at least 30 days prior to Visit 1 and is expected 
to be taken on the same regimen throughout the study period 
i. Any other medication known to cause ocular drying (e.g., antidepressants, 
beta blockers) except in the case that it was taken on a stable dosing regimen 
for at least 30 days prior to Visit 1 and is expected to be taken on the same 
regimen throughout the study period 
j. Restasis® 
k. Xiidra® 
l. CEQUA™ 
m. LipiFlow® or other similar meibomian gland dysfunction (MGD) therapy 
n. TrueTear® 
o. Corticosteroids (e.g., systemic steroids including intravenous, intramuscular, 
intraarticular, oral steroids; nasal steroids; facial topical steroids; 
dermatological steroids with high potency or large treatment areas); 
p. Tetracyclines (tetracycline, doxycycline, minocycline, etc.) 
10. Be monocular or have best corrected visual acuity greater than or equal to logMAR+0.7 
in either eye as assessed by the ETDRS scale at Visit 1; 
11. Have a severe/serious systemic disease, chronic illness or uncontrolled medical condition 
including, but not limited to, severe cardiopulmonary disease, poorly controlled 
hypertension, poorly controlled diabetes and/or clinically significant (CS) hematologic, 
renal or liver disease that in the opinion of the Investigator could interfere with study 
assessments or limit compliance; 
12. Be a woman who is pregnant, nursing or planning a pregnancy; 
13. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 5 (or early termination 
visit) if of childbearing potential. Non-childbearing potential is defined as a woman who 


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is permanently sterilized (e.g., has had a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy), or is post-menopausal (i.e., without menses for 12 consecutive months); 
14. Be a woman of childbearing potential who is not using an acceptable means of birth 
control. Acceptable methods of contraception include hormonal (e.g., oral, implantable, 
injectable, or transdermal contraceptives), mechanical (e.g., 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 females, abstinence might be regarded as 
an adequate method of birth control; however, if the subject became sexually active 
during the study, she must agree to use adequate birth control as defined above for the 
remainder of the study; 
15. Have a known hypersensitivity or contraindication to the investigational products (IPs) or 
their components; 
16. Have a condition or be in a situation which the Investigator felt may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study (e.g., any planned procedure or surgery during the 
study period); 
17. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days prior to Visit 1; 
18. Have previously participated in a clinical trial with IC265 (previously called PRT-2761); 
19. Be, in the opinion of the Investigator, unable or unwilling to comply with the study 
protocol, including participation in all study assessments, visits, and dosing, or be unable 
to instill eye drops successfully. Subject non-compliance with dosing during the run-in 
period, defined as < 80% or > 125% of expected doses taken, might be exclusionary if, in 
the opinion of the Investigator, the subject is likely to be non-compliant with subsequent 
dosing regimens or other study assessments; or 
20. Be an employee of the site that is directly involved in the management, administration, or 
support of this study or be an immediate family member of the same. 
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).  
If a subject discontinues participation in the study early, every attempt will be made to 
complete the exit procedures required at the final study visit (Visit 5). 
6.0 
STUDY PARAMETERS 
6.1 
EFFICACY ENDPOINTS 
The following endpoints will be tested in the study eye: 
• Fluorescein staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, and pre- 
to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the following 
regions: central, superior, inferior, temporal, nasal, corneal sum, conjunctival sum, 
and total eye score 


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• Ocular discomfort and dry eye symptoms at Visits 3, 4 (pre-CAE, post-CAE, and pre- 
to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE)  
• Lissamine green staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, and 
pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the 
following regions: central, superior, inferior, temporal, nasal, corneal sum, 
conjunctival sum, and total eye score 
• Tear film break-up time at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), 
and 5 (pre-CAE, post-CAE, and pre- to post-CAE)  
• Conjunctival Redness at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 
5 (pre-CAE, post-CAE, and pre- to post-CAE), and mean change from baseline Visit 
2 (Day 1) pre-CAE to Visit 5 (Day 85) pre-CAE 
• Ocular Surface Disease Index (OSDI) at Visits 3, 4, and 5 (pre-CAE) 
• Schirmer’s test at Visit 3, 4, and 5  
• Ocular discomfort during CAE at Visits 4 and 5 
• Daily diary symptom score 
6.2 
SAFETY MEASURES 
The following safety measures will be evaluated in both eyes: 
• 
Visual acuity 
• 
Slit-lamp evaluation 
• 
Adverse event query 
• 
Intraocular pressure 
• 
Undilated fundoscopy 
• 
Drop comfort assessment after randomization at Visit 2, 3, 4, and 5 
7.0 
STUDY MATERIALS 
7.1 
STUDY TREATMENTS 
7.1.1 Study Drug Formulation 
All arms will be double-masked. Subjects will be randomized 1:1 into: 
• IC265 Ophthalmic Solution 1%; BID 
• Placebo Ophthalmic Solution (Vehicle); BID  
IC265 Ophthalmic Solution will be formulated as a sterile, non-preserved solution around pH 
6 for topical ophthalmic administration and is intended for clinical use. The study drug will 
be supplied in blow-fill seal ampoules, which allow for product administration directly to the 
eye. Each ampoule will contain a nominal volume of 0.27 mL.  
The excipients which will be used to manufacture IC265 Ophthalmic Solution will be 
standard excipients for use in ophthalmic solutions that comply with their respective USP / 
EP monographs. 
The placebo for IC265 Ophthalmic Solution contains all the same excipients used in the 
active formulation without the API. 


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7.1.2 Description of and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period. 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. The 
dosage and dosage regimen were selected based on positive efficacy results in the proof-of-
concept nonclinical studies. The proposed treatment period is 12 weeks. 
7.1.3 Instructions for Use and Administration 
• Subjects will receive placebo ophthalmic solution at Visit 1, and assigned a study 
drug kit at Visit 2, 3, and 4. 
• Subjects who are randomized must administer study drug bilaterally BID. At Visit 2, 
3, and 4, subjects will self-administer one dose of study drug in office. 
7.2 
LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, AND 
RETURN OR DISPOSAL OF INVESTIGATIONAL PRODUCT 
7.2.1 Labeling/Packaging 
Investigational product (IP) will be packaged and labeled into clinical kits. The primary 
packaging of the IC265 will be blow-fill-seal ampules with a fill volume of 0.27 mL. The 
secondary packaging is a foil pouch that contains three ampules in each pouch. 
Run-in Period 
For the run-in period, 6 pouches will be packaged in a 1-week clinical kit. Each subject will 
receive 2 kits.  
Treatment Period 
BID Dosing: For the treatment period, 6 pouches will be packaged in a 1-week clinical kit. 
Each subject will receive 12 kits.  
7.2.2 Storage of Investigational Product 
Ampoules must be stored at controlled room temperature from 15 oC to 25oC until the day of use. 
Any material remaining in the ampoule after use should be discarded. IC265 Ophthalmic Solution 
should be kept out of reach of children. Drug administration instructions and discarding 
information will be provided with each study. 
7.2.3 Accountability of Investigational Product 
The IP is to only be prescribed by the Principal Investigator (PI) or his/her named sub-
investigator(s), and is to only be used in accordance with this protocol. The IP must only be 
distributed to subjects properly qualified under this protocol to receive IP. 
The Investigator must keep an accurate accounting of the IP received from the supplier. This 
includes the amount of IP dispensed to subjects, amount of IP returned to the investigator by 
the subjects, and the amount returned or disposed upon the completion of the study. A 
detailed inventory must be completed for the IP. 
7.2.4 Return or Disposal of Investigational Product 
All IP (used or unused) will be returned to the sponsor or their designee. The return of IP will 
be specified in writing. 
7.3 
OTHER STUDY SUPPLIES 
Other study supplies include Schirmer’s test strips, sodium fluorescein, lissamine green, 
Fluress, Tropicamide, Daily diary. 


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8.0 
STUDY METHODS AND PROCEDURES 
8.1 
SUBJECT ENTRY PROCEDURES 
8.1.1 Overview 
Subjects as defined by the criteria in Section 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 study (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and subjects 
wishing to participate must give written informed consent using an informed consent form. 
The informed consent form 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 (Section 5.3 and 5.4). 
8.1.5 Methods for Assignment to Treatment Groups: 
Before the initiation of study run-in at Visit 1, each subject who provides written informed 
consent 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. Each subject who 
meets all the inclusion and none of the exclusion criteria at Visit 1 and Visit 2 will be 
assigned a randomization number at the end of Visit 2. Randomization number will be 
assigned manually and entered in the Screening and Enrollment log or automatically assigned 
using the Interactive Web Response System (IWRS). 
The site staff will dispense kit(s) required until the next visit. Both the randomization number 
and the dispensed study drug kit number(s) will be recorded on the subject’s source document 
and electronic case report form (eCRF). Subjects, Sponsor, CRO, and site personnel will be 
masked to treatment assignment. 
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 medical 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. 


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8.3 
EXAMINATION PROCEDURES 
An Informed Consent Form (ICF) must be signed and dated by the subject, the PI or designee 
and witness (if required) before any study-related procedures are performed. 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives 
Procedures listed below should be performed in the given order. See Appendix 1 for the 
Schedule of Visits and Measurements Appendix 2 for details on methodologies and grading 
systems. 
8.3.2 Visit 1: Day –14 ± 2 – CAE Screening  
All subjects will undergo the following screening assessments: 
Pre–CAE  
• Informed Consent/Health Insurance Portability and Accountability Act (HIPAA)  
• Demographic Data and Medical/Medication/Ocular History 
• Review of Inclusion/Exclusion Criteria 
• Urine Pregnancy Test (for females of childbearing potential): Women of childbearing 
potential must have a negative urine pregnancy test to continue in the study  
• Adverse Event (AE) Query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI Questionnaire 
• Visual Analog Scale (VAS) Symptom Assessment 
• Visual Acuity (ETDRS) 
• Conjunctival Redness 
• Slit Lamp Biomicroscopy  
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
• At least 15 minute wait between Schirmer’s test and CAE exposure 
• 90-minute CAE exposure 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE and every 5 
minutes thereafter 
Post–CAE 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  


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• Conjunctival Redness 
• Slit Lamp Biomicroscopy 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
• Intraocular Pressure (IOP) 
• Undilated Fundoscopy 
• Review of Inclusion/Exclusion Criteria  
• Run-in (Vehicle) and Diary Dispensation: Prior to discharge from the study site on 
Visit 1, subjects will be dispensed sufficient Run-in supply to last until Visit 2 and 
will be educated in diary recording and self–administration of vehicle run-in. Subjects 
will be instructed to self–administer one drop BID bilaterally until Visit 2. Subjects 
will be instructed NOT to instill run-in on the morning of their next scheduled study 
visit (Visit 2).  
• Subjects will be scheduled for Visit 2. 
8.3.3 Visit 2: Day 1 – CAE® Confirmation and Baseline 
Pre–CAE  
• Study Diary/Run-in Collection 
• Medical and Medication History Update 
• Review of Inclusion/Exclusion Criteria 
• Medical/medication history update 
• Physical Exam (HEENT) 
• AE query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI Questionnaire 
• VAS Symptom Assessment 
• Visual Acuity (ETDRS) 
• Conjunctival Redness 
• Slit Lamp Biomicroscopy  
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 


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• At least 15 minute wait between Schirmer’s test and CAE exposure 
• 90-minute CAE exposure; 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE and every 5 
minutes thereafter 
Post–CAE 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Slit Lamp Biomicroscopy 
• Conjunctival Redness 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
• Review of Inclusion/Exclusion Criteria  
• Randomization  
• Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site on 
Visit 2 (Day 1), randomized subjects will be educated in study drug diary recording 
and self–administration of study drug. Subjects will receive their assigned study drug 
kit with sufficient supply to last until Visit 3 
• Study Drug Instillation at the Study Site: Randomized subjects will self-administer 
their initial study drug dose bilaterally at the study site under supervision of a trained 
technician 
• Ora Calibra® Drop Comfort Scale 
• Subjects will be scheduled for Visit 3 
8.3.4 Safety Phone Follow-Up: Day 8, Day 29, and Day 64 
• AE Query 
8.3.5 Visit 3: Day 15 ± 2 
Pre–CAE 
• Study Diary Collection 
• Medical and Medication History Update 
• AE Query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI Questionnaire 
• VAS Symptom Assessment 
• Visual Acuity (ETDRS) 
• Conjunctival Redness 


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• Slit Lamp Biomicroscopy  
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• 90-minute CAE exposure 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE and every 5 
minutes thereafter 
Post–CAE 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Conjunctival Redness 
• Slit Lamp Biomicroscopy 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
• Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site on 
Visit 3, subjects will be re-educated in study drug diary recording and self–
administration of study drug. Subjects will receive their assigned study drug kit with 
sufficient supply to last until Visit 4. 
• Study Drug Instillation at the Study Site: Randomized subjects will self-administer 
their initial study drug dose bilaterally at the study site under supervision of a trained 
technician 
• Ora Calibra® Drop Comfort Scale 
• Subjects will be scheduled for Visit 4 
8.3.6 Visit 4: Day 43 ± 2 
Pre–CAE 
• Study Diary Collection 
• Medical and Medication History Update 
• AE Query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI Questionnaire 
• VAS Symptom Assessment 
• Visual Acuity (ETDRS) 
• Conjunctival Redness 
• Slit Lamp Biomicroscopy  


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• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• 90-minute CAE exposure 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE and every 5 
minutes thereafter 
Post–CAE 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Conjunctival Redness 
• Slit Lamp Biomicroscopy 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
• Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site on 
Visit 4, subjects will be re-educated in study drug diary recording and self–
administration of study drug. Subjects will receive their assigned study drug kit with 
sufficient supply to last until Visit 5. 
• Study Drug Instillation at the Study Site: Randomized subjects will self-administer 
their initial study drug dose bilaterally at the study site under supervision of a trained 
technician 
• Ora Calibra® Drop Comfort Scale 
• Subjects will be scheduled for Visit 5 
8.3.7 Visit 5: Day 85 ± 4 
Pre–CAE 
• Study Drug/Study Diary Collection 
• Medical and Medication History Update 
• Pregnancy Test (if applicable) 
• AE Query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI Questionnaire 
• VAS Symptom Assessment 
• Visual Acuity (ETDRS) 
• Conjunctival Redness 
• Slit Lamp Biomicroscopy  


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• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
• At least 15 minute wait between Schirmer’s test and CAE exposure 
• 90-minute CAE exposure; 
o Ora Calibra® Ocular Discomfort Scale upon entering the CAE and every 5 
minutes thereafter 
Post–CAE 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Conjunctival Redness 
• Slit Lamp Biomicroscopy 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
• IOP 
• Undilated Fundoscopy 
• Study Exit  
8.4 
SCHEDULE OF VISITS, MEASUREMENTS AND DOSING 
8.4.1 Scheduled Visits 
Refer to Appendix 1: Schedule of Visits and Measurements 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 
• IOP 
• Urine Pregnancy Test 
• Undilated Fundoscopy 
• Assessment of AEs 


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• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator 
8.5 
COMPLIANCE WITH PROTOCOL 
Subjects will be instructed on proper use of the subject Daily diary and proper instillation and 
storage of study drug at the end of Visits 1 through 4 and given written instructions. To assess 
dosing and symptom assessment compliance, the subject daily diaries will be collected at 
Visit 2, 3, 4, 5, and the subject’s used and unused study drug ampules will be collected at 
Visit 3, 4, and 5. Dosing compliance will be based on the used and unused ampule count. If 
the subject is less than 80% or more than 125% compliant with dosing based on the expected 
number of used ampules, then the subject will be deemed non-compliant and a dosing 
deviation should be recorded. Subjects will be reinstructed on dosing compliance and this 
will be documented in the source documents. These guidelines will be used by the 
Investigator for determining the subject’s necessary compliance for the study and for 
recording deviations from this compliance. 
A protocol deviation occurs when there is any non-adherence to a study procedure or 
schedule that is specified by the protocol. The term “protocol deviation” includes those 
departures from the protocol previously described by the term “protocol violation”; all 
departures from the protocol are now described as protocol deviations, regardless of the 
potential impact on subject safety. A Protocol Deviation Log shall be maintained by the 
site(s). Protocol deviations will be summarized in the final clinical study report. 
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 prior to their completion of the study due to: 
• subject request/withdrawal 
• AEs 
• protocol violations 
• administrative reasons (e.g., inability to continue, lost to follow up) 
• sponsor termination of study 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made to 
Ora and/or sponsor and will be clearly documented on the eCRF. 
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 5 visits over approximately a 14-week 
period (14 days pre-screening, 84 days of treatment). 


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8.9 
MONITORING AND QUALITY ASSURANCE 
During the course of the study an Ora monitor, or designee, will make routine site visits to 
review protocol compliance, assess IP accountability, and ensure the study is being conducted 
according to the pertinent regulatory requirements. The review of the subjects’ medical 
records will be performed in a manner that adequately maintains subject confidentiality. 
Further details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, 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. 
9.0 
ADVERSE EVENTS 
9.1 
ADVERSE EVENT (AE) 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an IP, without any judgment about causality. An AE can arise from any use of the 
IP (e.g., off-label use, use in combination with another drug or medical device) and from any 
route of administration, formulation, or dose, including an overdose. An AE can arise from 
any delivery, implantation, or use of a medical device, including medical device failure, 
subject characteristics that may impact medical device performance (e.g., anatomical 
limitations), and therapeutic parameters (e.g., energy applied, sizing, dose release, and 
anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded in the source document and on the appropriate pages of the case 
report form (CRF). Any clinically relevant deterioration in clinical finding is considered an 
AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning. 
Exacerbation of conditions related to the signs and symptoms of DED will not be reported as 
an AE. 
All AEs and their outcomes, regardless of causality or expectedness, must be reported to Ora 
and the Sponsor as required by the IRB/IEC, federal, state, or local regulations and governing 
health authorities and recorded on the appropriate case report form (CRF). Adverse events 
will be collected after the signing of the Informed Consent). 
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the subject. The assessment of 
severity is made irrespective of relationship to IP or seriousness of the event and should be 
evaluated according to the following scale: 


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• Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere 
with the subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, 
and interferes with the subject’s daily activities. 
9.1.2 Relationship to Investigational Product 
The Investigator must assess whether they consider an AE to be drug-related. In assessing 
this relationship, the Investigator must use information about the conditions/concurrent 
medication, and chronology of the event relative to drug. The investigator should initially 
classify the relatedness of an AE, but the final classification is subject to the Medical 
Monitor’s determination unless revised by the Sponsor, which has the ultimate responsibility 
for judging relatedness. The relationship of each AE to the IP should be determined by the 
investigator using these explanations: 
• Definitely Related: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, follows a known response pattern of the drug 
class, is confirmed by improvement on stopping the IP and no other reasonable cause 
exists. 
• Probably Related: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, follows a known response pattern of the drug 
class, is confirmed by improvement on stopping the IP and the suspect IP is the most 
likely of all causes. 
• Possibly Related: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, but could also have been produced by the subject’s 
clinical state or by other drugs administered to the subject. 
• Unlikely to be Related: Relationship uncertain to the investigational product. Likely 
to be related to factors other than investigational product, but cannot be ruled out with 
certainty. 
• Not Related: Concurrent illness, concurrent medication, or other known cause is 
clearly responsible for the AE, the administration of the IP and the occurrence of the 
AE are not reasonably related in time, or exposure to IP has not occurred. 
9.2 
SERIOUS ADVERSE EVENTS 
An AE is considered serious if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if 
less than 24 hours), unless the inpatient admission was pre-planned prior to the 
signing of the informed consent. 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 
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Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
• A congenital anomaly/birth defect 
• Death; 
• Is life-threatening; 
Note: An AE is considered “life-threatening” if, in the view of either the Investigator 
or Sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
9.2.1 Expectedness 
The expectedness of a SAE should be determined based upon existing safety information 
about the IP using these explanations: 
• Unexpected: An SAE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
• Expected: An SAE that is listed in the Investigational Brochure (IB) at the specificity 
and severity that has been observed. 
• Not applicable: An SAE unrelated to the IP. 
SAEs that are mentioned in the IB as occurring with a class of products or as anticipated from 
the pharmacological/mechanical (or other) properties of the product, but are not specifically 
mentioned as occurring with the particular product under investigation are to be considered 
unexpected. 
9.3 
PROCEDURES FOR REPORTING SERIOUS ADVERSE EVENTS 
All SAEs and their outcomes, regardless of causality or expectedness, must be reported to 
Ora and the Sponsor as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities and recorded on the appropriate case report form (CRF). 
Adverse events will be collected after the signing of the Informed Consent). 
9.3.1 Reporting a Serious Unexpected Suspected Adverse Reaction 
All SAEs that are both ‘suspected’ and ‘unexpected’ are to be reported to Ora, the Sponsor, 
and the IRB/IEC and the regulatory authorities 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 SAEs, regardless of relationship to the IP, must be immediately 
reported within 24 hours of awareness of the event. All information relevant to the SAE must 
be recorded on the appropriate CRFs. The investigator is obligated to pursue and obtain 
information requested by Ora and/or the sponsor in addition to that information reported on 
the CRF. All subjects experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify Ora and the Sponsor immediately using 
the contact information below; 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 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 IP; and inform the IRB of the SAE within their guidelines for reporting SAEs. 
Contact information for reporting SAEs: 
Name: 
Joseph B. Ciolino, MD 
Title: 
Medical Monitor 
Office Telephone: 
617-573-5575 
Mobile Phone: 
401-935-9662 
Office Facsimile: 
617-573- 4324 
Name: 
David Welch 
Title: 
Clinical Project Manager 
Office Telephone: 
(978) 685-8900 x 
Office Facsimile: 
(978) 689-0020 
Ora Safety 
safetygroup@oraclinical.com 
9.4 
PROCEDURES FOR UNMASKING (IF APPLICABLE) 
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 group 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. Ora and/or the study Sponsor must be informed immediately about 
any unmasking event. 
If an investigator identifies a medical need for unmasking the treatment assignment of a 
subject, he/she should contact Ora and/or the medical monitor prior to unmasking the identity 
of the IP, if possible. Ora will ask the site to complete and send them the Unmasking Request 
Form. Ora will notify the Sponsor, and jointly will determine if the unmasking request should 
be granted. They may consult the medical monitor as needed. The result of the request will be 
documented on the Unmasking Request Form. If approval is granted to unmask a subject, 
written permission via the Unmasking Request Form will be provided to the investigator. The 
investigator will unmask the subject using IWRS. The investigator will complete the 
Unmasking Memo form and include it in the subject’s study file and provide a copy for the 
Trial Master File (TMF). For each unmasked request, the reason, date, signature, and name of 
the person who unmasked the subject must be noted in the subject’s study file.  
Unmasked subjects will be discontinued from the study. Unmasked subjects will be followed 
for safety monitoring until resolution of the adverse event or study completion, whichever 
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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 or stabilization 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 subject is lost to follow-up, the investigator 
should make reasonable attempts to contact the subject via telephone, post, or certified mail. 
All follow-up will be documented in the subject’s source document. Non-serious 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. 
10.0 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSIS 
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. Efficacy analyses will be performed on the ITT population with 
observed data only. The ITT population may also be analyzed using the Last 
Observation Carried Forward (LOCF) imputation method and multiple imputation to 
assess sensitivity. 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. The 
PP population will be analyzed using observed data only for efficacy variables. 
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. The safety population will be 
analyzed for all safety assessments. Subjects in the Safety population will be analyzed 
as treated.  
The statistical analysis of safety data will be performed for the safety population. The 
analysis of efficacy data will be performed for the ITT population and on the PP population 
as sensitivity analyses. 
10.2 
STATISTICAL HYPOTHESES  
This is an exploratory study with no primary or secondary endpoints. The following 
endpoints will be tested in the study eye: 
• Fluorescein staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, and pre- 
to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the following 
regions: central, superior, inferior, temporal, nasal, corneal sum, conjunctival sum, 
and total eye score 
• Ocular discomfort and dry eye symptoms at Visits 3, 4 (pre-CAE, post-CAE, and pre- 
to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) 


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• Lissamine green staining (Ora Calibra scale) at Visits 3, 4 (pre-CAE, post-CAE, and 
pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the 
following regions: central, superior, inferior, temporal, nasal, corneal sum, 
conjunctival sum, and total eye score 
• Tear film break-up time at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), 
and 5 (pre-CAE, post-CAE, and pre- to post-CAE)  
• Conjunctival Redness at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 
5 (pre-CAE, post-CAE, and pre- to post-CAE), and mean change from baseline Visit 
2 (Day 1) pre-CAE to Visit 5 (Day 84) pre-CAE 
• Ocular Surface Disease Index (OSDI) at Visits 3, 4, and 5 (pre-CAE) 
• Schirmer’s test at Visit 3, 4, and 5 
• Ocular discomfort during CAE at Visits 4 and 5 
• Daily diary symptom score 
10.3 
SAMPLE SIZE  
Approximately 80 subjects will be screened to enroll 40 subjects (20 subjects in each group). 
This is a Phase 2 study for which no formal sample size calculation has been performed. The 
sample size chosen was not based on statistical considerations, but is based on historical 
experience. 
10.4 
STATISTICAL ANALYSIS 
10.4.1 General Considerations 
Continuous variables will be summarized descriptively using number of subjects (n), mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using counts and percentages. 
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and AEs will be 
coded to Medical Dictionary for Regulatory Authorities (MedDRA) MedDRA and World 
Health Organization (WHO) Drug dictionaries, as appropriate.  
Baseline measures are defined as the last non-missing measure prior to the initiation of 
randomized study treatment, usually at Visit 2. Change from baseline will be calculated as 
follow-up visit value minus baseline value. Treatment comparisons between active and 
vehicle will be calculated as active minus vehicle. 
All analyses will be 2-sided at a significance level of 0.05 unless otherwise specified. For all 
efficacy analyses, 95% confidence intervals on the difference between each dose of IC265 
and vehicle will be provided. 
10.4.2 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: 
Study 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 study eye will be the eye with the worst (higher) 
total corneal fluorescein staining, based on the sum of the inferior, superior, and central 


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regions, at baseline (Visit 2) pre-CAE. If the total corneal staining is the same in both eyes, 
then the right eye will be selected as the study eye. 
10.4.3 Missing Data  
Missing data will be imputed using Last Observation Carried Forward (LOCF) on the ITT 
population for primary analyses. 
Sensitivity analyses of the primary analyses and important secondary comparisons will include 
the following in order to provide a robust understanding of the impact of missing and spurious 
data:  
• Using observed data only on the ITT population 
• Using multiple imputation on the ITT population 
• Using observed data only on the PP population.  
No imputation will be used for safety endpoints. 
10.4.4 Multiplicity Consideration 
As this is an exploratory study with no primary or secondary endpoints, there will be no 
multiplicity adjustments and all analyses are considered hypothesis-generating. 
10.4.5 Efficacy Analyses 
The method of analysis for efficacy endpoints will be based on the distribution of the 
individual variable for analysis. Variables recorded on a continuous scale will be analyzed at 
each visit using two-sample t-tests and Wilcoxon rank sum tests. Each visit and treatment 
group will be summarized using descriptive statistics for the ITT population with observed 
data only. Changes from baseline will be summarized by visit and treatment using descriptive 
statistics and analyzed by visit using ANCOVA models with baseline value and treatment 
group, two sample t-tests and Wilcoxon rank sum tests on the ITT population with observed 
data only. 
For multinomial outcome variables, a generalized linear model will be used, and the 
distribution will be specified as multinomial.  
The ITT population may also be analyzed using LOCF imputation and multiple imputation to 
assess sensitivity as detailed further in the statistical analysis plan (SAP). Analyses using the 
PP population with observed/recorded data only may also be conducted. 
10.4.6 Safety Variables 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. Frequencies and percentages will be provided per treatment group of 
subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs 
causing premature discontinuation will be provided by treatment group. An adverse event is 
treatment emergent if it occurs or worsens after the first dose of randomized study treatment. 
Furthermore, frequencies will be given of subjects with TEAEs by system organ class and 
preferred term, by system organ class, preferred term and maximal severity, by system organ 
class, preferred term for treatment-related adverse events (AEs), by system organ class and 
preferred term for serious adverse events (SAEs); and by system organ class, preferred term, 
and day of onset. Separate analyses will be performed for ocular and non-ocular adverse 
events. 
The incidence of patients who experience a TEAE of interest over the 12-week post-
treatment observation period will be compared between the IC265 and placebo groups. A 
generalized linear model will be used, and the distribution will be specified as binomial.  


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The incidence of patients who experience a composite of one or more MedDRA preferred 
terms of interest over the 12-week post-treatment observation period will be compared 
between the IC265 and placebo groups. A generalized linear model will be used. 
Other safety endpoints will be summarized by treatment and visit using descriptive statistics. 
Change or shift from baseline will also be summarized where appropriate. For assessments 
performed by eye, both eyes will be summarized separately. 
10.4.7 Interim Analyses 
There will be no interim analyses in this study. 
11.0 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical Practices 
(GCPs), including the International Conference on Harmonisation (ICH) Guidelines, and in 
general, consistent with the Declaration of Helsinki. In addition, all applicable local, state, 
and federal requirements relevant to the use of IP in the countries involved will be addressed. 
11.1 
PROTECTION OF HUMAN SUBJECTS 
11.1.1 Subject Informed Consent 
Informed consent must take place before any study specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject prior to enrollment 
into the study.  
All informed consent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB 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 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 Sponsor and provided in writing 
by Ora and/or Sponsor prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 Code of Federal 
Regulations Part 56.103). The Investigator must obtain appropriate IRB approval before 
initiating the study and re-approval at least annually. 
Only an IRB 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 is in accordance with local, state, and federal laws and 
regulations. 


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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, other domestic government agencies, and other foreign regulatory 
agencies (when relevant) will be granted direct access to the subject’s original medical and 
study records for verification of the data and/or clinical study 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 IP 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 electrocardiograms. The Investigator’s copy of the CRFs 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 IP, and copies of CRFs should be maintained on file for at least two years after 
the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region; or until at least two years have 
elapsed since the formal discontinuation of clinical development of the IP. These documents 
will be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with the sponsor. It is the 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 
RECORDING OF DATA ON SOURCE DOCUMENTS AND CASE 
REPORTS FORMS (CRFS) 
The Investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, and all study-related material. All study 
data should also be attributable, legible, contemporaneous, and original. Recorded datum 
should only be corrected in a manner that does not obliterate, destroy, or render illegible the 
previous entry (e.g., by drawing a single line through the incorrect entry and writing the 
revision next to the corrected data). An individual who has corrected a data entry should 
make clear who made the correction and when, by adding to the correction his/her initials as 
well as the date of the correction. 
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 be entered in eCRF 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. 


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11.6 
PUBLICATIONS 
All data derived from the study will be the property of the sponsor and must be kept strictly 
confidential. The Investigator must not submit any of the data from this study for publication 
without prior consent of the Sponsor. The Sponsor will have the final decision regarding any 
manuscript and publication. 
 


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12.0 
REFERENCES 
Craig, J. P., K. K. Nichols, E. K. Akpek, B. Caffery, H. S. Dua, C. K. Joo, Z. Liu, J. D. 
Nelson, J. J. Nichols, K. Tsubota and F. Stapleton (2017). "TFOS DEWS II Definition and 
Classification Report." Ocul Surf 15(3): 276-283. 
Fiscella, R. G. (2011). "Understanding dry eye disease: a managed care perspective." Am J 
Manag Care 17 Suppl 16: S432-439. 
Hoellenriegel, J., G. P. Coffey, U. Sinha, A. Pandey, M. Sivina, A. Ferrajoli, F. Ravandi, W. 
G. Wierda, S. O'Brien, M. J. Keating and J. A. Burger (2012). "Selective, novel spleen 
tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and 
migration." Leukemia 26(7): 1576-1583. 
Markham, A. (2018). "Fostamatinib: First Global Approval." Drugs 78(9): 959-963. 
Messmer, E. M. (2015). "The pathophysiology, diagnosis, and treatment of dry eye disease." 
Dtsch Arztebl Int 112(5): 71-81; quiz 82. 
Pflugfelder, S. C. (2008). "Prevalence, burden, and pharmacoeconomics of dry eye disease." 
Am J Manag Care 14(3 Suppl): S102-106. 
Reilly, M. P., U. Sinha, P. Andre, S. M. Taylor, Y. Pak, F. R. Deguzman, N. Nanda, A. 
Pandey, M. Stolla, W. Bergmeier and S. E. McKenzie (2011). "PRT-060318, a novel Syk 
inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse 
model." Blood 117(7): 2241-2246. 
Ulanova, M., F. Duta, L. Puttagunta, A. D. Schreiber and A. D. Befus (2005). "Spleen 
tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis." Expert Opin Ther 
Targets 9(5): 901-921. 


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Protocol IC265-0001 
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13.0 
APPENDICES 
13.1 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
Procedure 
Visit 1 
Day -14 ± 2 
Visit 2 
Day 1 
Day 8 
Visit 3 
Day 15 ± 2 
Day 29 
Visit 4 
Day 43 ± 2 
Day 64 
Visit 5 
Day 85 ± 4/Early Termination 
 
Pre-
CAE 
Post -
CAE 
Pre-
CAE 
Post-
CAE 
Phone 
Call 
Pre-
CAE 
Post-
CAE 
Phone 
Call 
Pre-
CAE 
Post-
CAE 
Phone 
Call 
Pre-CAE 
Post-CAE 
Informed Consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical / Medication History and Demographic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Run-in Collection 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug Collection 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Diary Collection 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Medical / Medication History Update 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Adverse Event Query 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Pregnancy Test 
X1 
 
 
 
 
 
 
 
 
 
 
X1 
 
Physical Exam (HEENT) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Ora Calibra™ Ocular Discomfort & 4-Symptom 
Questionnaire 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
OSDI© Questionnaire 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Visual Acuity (ETDRS) 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Review of Qualification Criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Slit-lamp Biomicroscopy 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
TFBUT 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Fluorescein Staining 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Lissamine Green Staining 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Conjunctival Redness  
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Tear Collection 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
CAE® Exposure 
X 
X 
 
X 
 
X 
 
X 
Ora Calibra™ Ocular Discomfort Scale 
X2 
X2 
 
X2 
 
X2 
 
X2 
Unanesthetized Schirmer’s Test 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Intraocular Pressure 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Undilated Fundus Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
X 


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Run-in Article Dispensation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomized Study Drug Instillation 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Drop Comfort Assessment 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Study Drug Dispensation 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Diary Dispensation 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Exit Subject from Study 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X1 =  For females of childbearing potential, X2  =  Procedure started at time 0 and then conducted every 5 minutes thereafter during the 90 minute CAESM exposure 
 


IACTA Pharmaceuticals, Inc. 
 
Protocol IC265-0001 
IC265 Ophthalmic Solution 
 
IND 130141 
 
13.2 
APPENDIX 2: EXAMINATION PROCEDURES, TESTS, & 
EVALUATIONS  
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart. The procedure used will be consistent with the 
recommendations provided for using the ETDRS eye chart. VA should be evaluated at the 
beginning of each visit in the study (i.e., prior to slit-lamp examination). VA testing should 
be done with most recent correction. 
Equipment 
The VA chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", e.g., from 
Prevent Blindness) wall charts are used, the subject viewing distance should be exactly 
10 feet (or as specified by the manufacturer). In all cases, for purposes of standardizing the 
testing conditions during the study, all sites must use only the 'R' charts, and the right eye 
should be tested first. For reflectance (wall) charts, the chart should be placed frontally and 
well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
subject should attempt to read each letter, line-by-line, left to right, beginning with line 1 at 
the top of the chart. The subject should be told that the chart has letters only, no numbers. If 
the subject reads a number, he or she should be reminded that the chart contains no numbers, 
and the examiner should then request a letter in lieu of the number. The subject should be 
asked to read slowly, so as to achieve the best identification of each letter. He/she is not to 
proceed to the next letter until he/she has given a definite response. 
If the subject changes a response (e.g., that was a "C" not an "O") before he has read aloud 
the next letter, then the change must be accepted. If the subject changes a response having 
read the next letter, then the change is not to be accepted. The examiner should never point to 
the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject says 
he or she cannot read a letter, he or she should be encouraged to guess. If the subject 
identifies a letter as 1 of 2 letters, he or she should be asked to choose 1 letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that eye. 
However, all letters on the last line should be attempted as letter difficulties vary and the last 
may be the only one read correctly. The number of letters missed or read incorrectly should 
be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To 
this value will be added the number "N x 0.02" where 'N' represents the total number of 
letters missed up to and included in the last line read. This total sum represents the logMAR 
VA for that eye. 
For example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 
line. 
 
 


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Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as 
well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, all 
VA assessments at a single site must be consistently done using the same lighting conditions 
and same correction if possible during the entire study. If the same correction cannot be used 
(i.e., a subject forgets his glasses), the reason for the change in correction should be 
documented. 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with study 
parameters or otherwise confound the data as determined by the investigator) or not clinically 
significant (NCS). The following will be examined:  
• Cornea  
• Conjunctiva 
• Anterior Chamber 
• Iris 
• Lens 
• Eyelid 
External magnification and biomicroscopy will be performed using a slit-lamp. Magnification 
will be consistent with standard clinical practice. The subject will be seated. 
Undilated Fundoscopy 
Undilated fundus exams will be performed using indirect ophthalmoscopy. The Investigator 
will make observations of the vitreous, retina, macula, choroid and optic nerve.  
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically 
significant (as determined by the Investigator that may interfere with study parameters or 
otherwise confound the data) and those that are not clinically significant will be described. 
An indirect Fundoscopy examination should be performed if retinal disease is detected.  
• Vitreous: Examination should emphasize the visual axis.  
• Retina, Macula, Choroid: Include an observation of the retina and its blood vessels. 
Eyes should be excluded from the study if active inflammation is present.  
• Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
 
Intraocular Pressure (IOP) 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg. A single measurement is made to obtain 
a determination of IOP. The same tonometer employing the investigator’s standard technique 


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will be used throughout the study. In addition, all reasonable efforts will be made to have the 
same examiner obtain all IOP measurements for a given subject. 
Unanesthetized Schirmer’s Test  
Schirmer Tear Test will be performed according to the following procedure: 
• Using a sterile Tear Flo Schirmer test strip, a bend in the strip will be made in line 
with the notch in the strip. 
• The subject will be instructed to gaze up and in. 
• The Schirmer test strip will be placed in the lower temporal lid margin of each eye 
such that the strip fits tightly. Subjects will be instructed to close their eyes. 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the 
moistened area will be recorded (mm) for each eye. 


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Ocular Surface and Disease Index© (OSDI©) for Dry Eye 
 
 


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Visual Analog Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to 
study drug instillation) at all visits.  
The subject will be asked to rate each ocular symptom due to ocular dryness by placing a 
vertical mark on the horizontal line to indicate the level of discomfort. 0% corresponds to “no 
discomfort” and 100% corresponds to “maximal discomfort.”  
 
Tear Film Break-Up Time (TFBUT)  
The examiner will instill 5 L of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. To thoroughly mix the fluorescein with the tear 
film, the subject will be instructed to blink several times. In order to achieve maximum 
fluorescence, the examiner should wait approximately 30 seconds after instillation before 
evaluating TFBUT.   
With the aid of a slit-lamp, the examiner will monitor the integrity of the tear film, noting the 
time it takes to form micelles from the time that the eye is opened. TFBUT will be measured 
in seconds using a stopwatch and a digital image recording system for the right eye followed 
by the left eye. A Wratten #12 yellow filter will be used to enhance the ability to grade 
TFBUT.  
For each eye, 2 measurements will be taken and averaged unless the 2 measurements are > 2 
seconds apart and are each < 10 seconds, in which case, a third measurement would be taken 
and the 2 closest of the 3 would be averaged. 
 
 


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Fluorescein Staining  
The examiner will instill 5 L of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. In order to achieve maximum fluorescence, the 
examiner should wait approximately 3-5 minutes after instillation before evaluating 
fluorescein staining. A Wratten #12 yellow filter will be used to enhance the ability to grade 
fluorescein staining. The staining will be graded with the Ora Calibra® Corneal and 
Conjunctival Staining Scale. 
Ora proprietary scales – Not for distribution without permission 
Ora Calibra® Ocular Discomfort Scale for Dry Eye 
This procedure will be performed according to Ora, Inc. Standard Operating Procedures 
(SOPs) and/or guidance documents. 
Ocular discomfort scores will be subjectively graded by the subjects according to the 
following scale, rating each eye separately.  
0 
No discomfort 
1 
Intermittent awareness 
2 
Constant awareness 
3 
Intermittent discomfort 
4 
Constant discomfort 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire for Dry Eye 
This procedure will be performed according to Ora, Inc. Standard Operating Procedures 
and/or guidance documents. 
At each day during the at-home dosing period, subjects will grade the severity of their dry 
eye syndrome symptoms in their diary in the morning and in the evening, before instilling the 
study drug.  
Subjects will rate the severity of each of the following symptoms, with regard to how both 
their eyes feel, in general – overall ocular discomfort, burning, dryness, grittiness and 
stinging according to the following 6-point (0 to 5) scale where 0 = none and 5 = worst. 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
(None)  
 
 
 
 
 
 
 
   (Worst) 


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Ora Calibra® Corneal and Conjunctival Staining Scale for Grading of Fluorescein 
Staining 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance documents. 
The following scale will be used to grade staining of the ocular surface (areas A, B, C, D, and 
E). Half (0.5) grade increments may be used.  
None  
0 = no staining 
Trace  
1 = occasional 
Mild  
2 = countable 
Moderate  
3 = uncountable, but not confluent 
Severe  
4 = confluent 
 
Staining areas: 
 
Staining Areas 
Ocular Structure 
Position 
A – Inferior 
Cornea 
4-8 o’clock, extending 2 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
4-8 o’clock, extending 2 mm towards the 
center 
B – Superior 
Cornea 
8-4 o’clock, extending 3 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
8-10 o’clock and 2-4 o’clock, extending 1 
mm onto the conjunctiva; 
10-2 o’clock, extending 2 mm onto the 
conjunctiva 
C – Central 
Cornea 
Central cornea 
D – Temporal 
Conjunctiva 
Triangular wedge of temporal conjunctiva 
E – Nasal 
Conjunctiva 
Triangular wedge of nasal conjunctiva 
 
Lissamine Green Staining  
The Investigator will instill 10 L of lissamine green solution or place a lissamine strip into 
the inferior conjunctival cul-de-sac and wait approximately 30 seconds before evaluating 
staining. The subject will be instructed to blink several times to distribute the lissamine green. 
The staining will be graded with the Ora Calibra® Corneal and Conjunctival Staining Scale.  


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Ora Calibra® Conjunctival Redness Scale for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance documents. 
None  
0 = Normal, without vasodilation 
Trace  
1 = Trace ciliary or conjunctival vasodilation 
Mild  
2 = Broad ciliary vasodilation; 
Moderate  
3 = Broad ciliary and slight, horizontal conjunctival vasodilation 
Severe  
4 = Broad ciliary and prominent, horizontal conjunctival 
vasodilation 
Half (0.5) unit increments are allowed. 
Drop Comfort Assessments 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance documents. 
Subject-Reported Drop Comfort Scale 
Drop comfort will be assessed for each eye immediately upon instillation, and at 1 and 2 
minutes following initial dosing at Visits 1, 2, 3, and 4 using the Ora Calibra™ Drop Comfort 
Scale. 
Ora Calibra® Drop Comfort Scale 
 
 
Subject Diary 
Subject will be asked to complete a dosing diary daily between Visit 1 and Visit 5. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Very Comfortable 
Very Uncomfortable 


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13.3 
APPENDIX 3: PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 


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13.4 
APPENDIX 4: SPONSOR AND ORA APPROVALS 
Protocol Title: 
A Phase 2, Single-Center, Randomized, Double-
Masked, Placebo-Controlled Study to Assess the 
Safety and Efficacy of IC265 Ophthalmic Solution 1% 
in Subjects with Dry Eye Disease 
IND Number 
130141 
Final Date (Version 1.0):  
12 Jun 2023 
This clinical study protocol was subject to critical review and has been approved by the sponsor. The 
following personnel contributed to writing and/or approving this protocol. 
 
 
Signed:                               
Date:                  
 
George Ousler 
Senior Vice President, Anterior Segment 
Ora, Inc. 
 
 
 
 
 
Signed:                              
Date:                  
 
Eric Carter, 
Chieft Medical Officer 
IACTA Pharmaceuticals, Inc. 
 
 
 
 
 
 
Signed:                              
Date:                  
 
Anoshie Ratnayake, 
Medical Monitor 
IACTA Pharmaceuticals, Inc. 
 
 
 
 


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13.5 
APPENDIX 5: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Phase 2, Single-Center, Randomized, Double-
Masked, Placebo-Controlled Study to Assess the 
Safety and Efficacy of IC265 Ophthalmic Solution 1% 
in Subjects with Dry Eye Disease 
IND Number 
130141 
Final Date (Version 1.0):  
12 Jun 2023 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to maintain 
all information supplied by Ora and the sponsor in confidence and, when this information is 
submitted to an Institutional Review Board (IRB), Ethical Review Committee (ERC) or 
another group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
 
Signed: _________________ 
Date: ____________________ 
 
 

SAP_001.pdf: 
NCT05992922 
 
FORM.152.06  
STATISTICAL ANALYSIS PLAN  
A Phase 2, Single-Center, Randomized, Double-Masked, Placebo-
Controlled Study to Assess the Safety and Efficacy of IC265 
Ophthalmic Solution 1% in Subjects Diagnosed with Dry Eye Disease 
 
 
 
Sponsor: 
 
IACTA Pharmaceuticals, Inc. 
 
 
 
19900 MacArthur Blvd, Suite 550 
 
 
 
Irvine, CA 92612 
 
 
Protocol Number: 
23-110-0002 
 
 
Author:  
 
Kay Jackson 
 
 
 
Biostatistician 
Statistics & Data Corporation 
 
Date: 
 
 
05FEB2023 
Version: 
 
0.3 
 


NCT05992922 
 
 
 
Page 2 of 27 
A Phase 2, Single-Center, Randomized, Double-Masked, Placebo-Controlled Study to Assess the 
Safety and Efficacy of IC265 Ophthalmic Solution 1% in Subjects Diagnosed with Dry Eye Disease 
Protocol Number: 
23-110-0002 
 
SAP Version:  
0.3 
SAP Date: 
 
05FEB2023 
 
Statistical Analysis Plan Approval 
 
 
 
Prepared by:  
 
 
 
 
 
 
 
 
 
 
Kay Jackson 
 
 
 
 
Date 
 
 
Biostatistician 
 
 
Statistics & Data Corporation 
 
 
 
 
Reviewed by:  
 
 
 
 
 
_____________ 
 
 
Eric Nowicki, PhD 
 
 
 
Date 
 
 
Sr. Director, Biostatistics 
 
 
Statistics & Data Corporation 
 
 
 
 
Reviewed by:  
 
 
 
 
 
_____________ 
 
 
Ahren Velasco  
 
 
 
Date 
 
 
Sr. Biostatistics Quality Control Specialist 
 
 
Statistics & Data Corporation 
 
 
 


Protocol 23-110-0002 SAP, Version 0.3 
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Approved by:  
 
 
 
 
 
_____________ 
 
 
Eric Carter 
 
 
 
 
Date 
 
 
Chief Medical Officer 
 
 
IACTA Pharmaceuticals, Inc. 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
Anoshie Ratnayake 
 
 
 
Date 
Medical Monitor 
 
 
IACTA Pharmaceuticals, Inc. 
 


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Table of Contents 
Table of Contents ................................................................................................................................. 4 
List of Abbreviations ............................................................................................................................. 6 
1. 
Introduction ............................................................................................................................ 7 
2. 
Study Objectives ................................................................................................................... 7 
3. 
Study Endpoints .................................................................................................................... 7 
3.1 
Primary Endpoints .............................................................................................................7 
3.2 
Secondary Endpoints ........................................................................................................7 
3.3 
Efficacy Endpoints .............................................................................................................7 
3.4 
Safety Endpoints ...............................................................................................................8 
3.5 
Statistical Hypotheses .......................................................................................................8 
4. 
Study Design and Procedures .............................................................................................. 8 
4.1 
General Study Design .......................................................................................................8 
4.2 
Schedule of Visits and Assessments ................................................................................9 
4.3 
Study Treatments ..............................................................................................................9 
5. 
Sample Size .......................................................................................................................... 9 
6. 
Data Preparation ................................................................................................................... 9 
6.1 
Input Data ..........................................................................................................................9 
6.2 
Output Data .....................................................................................................................10 
7. 
Analysis Populations ........................................................................................................... 10 
7.1 
Intent-to-Treat Population ...............................................................................................10 
7.2 
Safety Population ............................................................................................................10 
8. 
General Statistical Considerations ...................................................................................... 10 
8.1 
Unit of Analysis ................................................................................................................10 
8.2 
Missing or Inconclusive Data Handling ...........................................................................10 
8.2.1 
Missing Efficacy Assessments ................................................................................... 10 
8.2.2 
Missing Safety Assessments ..................................................................................... 11 
8.3 
Definition of Baseline.......................................................................................................11 
8.4 
Data Analysis Conventions .............................................................................................11 
8.5 
Adjustments for Multiplicity ..............................................................................................11 
9. 
Disposition of Subjects ........................................................................................................ 11 
10. 
Demographics and Physical Examination........................................................................... 12 
10.1 
Demographic Variables ...................................................................................................12 
10.2 
Physical Examination ......................................................................................................12 
11. 
Medical History and Concomitant Medications ................................................................... 13 
11.1 
Medical History ................................................................................................................13 


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11.2 
Concomitant Medications ................................................................................................13 
11.3 
Concomitant Procedures .................................................................................................13 
12. 
Dosing Compliance and Treatment Exposure .................................................................... 14 
12.1 
Dosing Compliance .........................................................................................................14 
12.2 
Treatment Exposure ........................................................................................................14 
13. 
Exploratory Efficacy Analyses ............................................................................................. 15 
13.1 
Primary Analysis of Exploratory Efficacy Variables ........................................................15 
13.1.1 
Fluorescein Staining (Ora Calibra® Scale)................................................................. 15 
13.1.2 
Ocular discomfort and dry eye symptoms ................................................................. 15 
13.1.3 
Lissamine Green Staining (Ora Calibra® Scale) ........................................................ 15 
13.1.4 
Tear Film Break-Up Time........................................................................................... 16 
13.1.5 
Conjunctival Redness ................................................................................................ 16 
13.1.6 
Ocular Surface Disease Index (OSDI) ....................................................................... 16 
13.1.7 
Unanesthetized Schirmer’s Test ................................................................................ 17 
13.1.8 
Ocular Discomfort During CAE .................................................................................. 17 
13.1.9 
Daily Diary Symptom Score ....................................................................................... 17 
13.2 
Sensitivity Analysis of Efficacy Variable(s) .....................................................................17 
14. 
Safety Analyses................................................................................................................... 18 
14.1 
Adverse Events ...............................................................................................................18 
14.2 
Visual Acuity ....................................................................................................................19 
14.3 
Slit-Lamp Biomicroscopy .................................................................................................19 
14.4 
Undilated Fundoscopy.....................................................................................................19 
14.5 
Intraocular Pressure ........................................................................................................19 
14.6 
Drop Comfort Scale Assessment ....................................................................................20 
15. 
Other Data ........................................................................................................................... 20 
15.1 
Physical Examination ......................................................................................................20 
15.2 
Visual Analog Scale ........................................................................................................20 
16. 
Interim Analyses .................................................................................................................. 20 
17. 
Changes from Protocol-Stated Analyses ............................................................................ 20 
18. 
References .......................................................................................................................... 21 
19. 
Revision History .................................................................................................................. 21 
20. 
Tables .................................................................................................................................. 21 
21. 
Listings ................................................................................................................................ 23 
22. 
Figures................................................................................................................................. 25 
23. 
Appendices .......................................................................................................................... 26 
23.1 
Appendix 1: Schedule of Visits and Measurements .......................................................26 
 


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List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BID 
Bis in die (Twice Daily) 
CAE 
Controlled Adverse Environment 
CFB 
Change from Baseline 
CI 
Confidence Interval 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NCS 
Not Clinically Significant 
QD 
Quaque die (Once Daily) 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
RDC 
Remote Data Capture 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
VA 
Visual Acuity 
WHODrug 
World Health Organization Drug Dictionary 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe in detail the planned analyses and reporting 
for protocol 23-110-0002, Version 3.0 dated 22AUG2023. 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 clinical study report. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports. 
The decision to terminate protocol 23-110-0002 was determined 16NOV2023 due to the emergent adverse 
events of Epithelial Haziness. Details on how the termination affected the protocol-state analyses can be 
found in Section 17. 
2. Study Objectives 
The objective of this study is to compare the safety and efficacy of IC265 Ophthalmic Solution 1% to placebo 
for the treatment of the signs and symptoms of dry eye disease. 
3. Study Endpoints 
3.1 
Primary Endpoints 
As this is an exploratory study, there are no primary endpoints. 
3.2 
Secondary Endpoints 
As this is an exploratory study, there are no secondary endpoints. 
3.3 
Efficacy Endpoints 
The efficacy endpoints include the following: 
• 
Fluorescein staining (Ora Calibra® scale) at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), 
and 5 (pre-CAE, post-CAE, and pre- to post-CAE) in the following regions: central, superior, inferior, 
temporal, nasal, corneal sum, conjunctival sum, and total eye score 
• 
Ocular discomfort and dry eye symptoms at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), 
and 5 (pre-CAE, post-CAE, and pre- to post-CAE) 
• 
Lissamine green staining (Ora Calibra® scale) at Visits 3, 4 (pre- CAE, post-CAE, and pre- to post-
CAE), and 5 (pre-CAE, post- CAE, and pre- to post-CAE) in the following regions: central, superior, 
inferior, temporal, nasal, corneal sum, conjunctival sum, and total eye score 


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• 
Tear film break-up time (TFBUT) at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 5 
(pre-CAE, post-CAE, and pre- to post- CAE) 
• 
Conjunctival Redness at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 5 (pre-CAE, 
post-CAE, and pre- to post- CAE), and mean change from baseline Visit 2 (Day 1) pre-CAE to Visit 
5 (Day 84) pre-CAE 
• 
Ocular Surface Disease Index (OSDI) at Visits 3, 4, and 5 (pre- CAE) 
• 
Schirmer’s test at Visit 3, 4, and 5 
• 
Ocular discomfort during CAE at Visits 4 and 5 
• 
Daily Diary Symptom Score 
3.4 
Safety Endpoints 
The safety endpoints include the following: 
• 
Visual acuity 
• 
Slit-lamp evaluation 
• 
Adverse event query 
• 
Intraocular pressure 
• 
Undilated fundoscopy 
• 
Drop comfort assessment after randomization at Visit 2, 3, 4, and 5 
3.5 
Statistical Hypotheses 
The clinical hypotheses for this study is that IC265 Ophthalmic Solution 1% twice daily (BID) is superior to 
its vehicle (BID) for the efficacy endpoints.  
4. Study Design and Procedures 
4.1 
General Study Design 
This is a Phase 2, single-center, double-masked, randomized, placebo-controlled clinical study. Subjects 
will be randomized to one of the following treatment arms at Visit 2 (Day 1): 
• 
IC265 Ophthalmic Solution 1%: 1 drop BID bilaterally (N=~20)  
• 
Placebo Ophthalmic Solution (Vehicle): 1 drop BID bilaterally (N=~20) 
Approximately 40 subjects will be randomly assigned to one of the two groups (1:1) to receive either IC265 
Ophthalmic Solution 1% or placebo solution as topical ophthalmic drops administered bilaterally BID for 12 
weeks. Subjects, Sponsor, Contract Research Organization (CRO), and site personnel will be masked to 
treatment assignment. 
During the 14-day study run-in period prior to randomization, all subjects will receive Placebo Ophthalmic 
Solution (Vehicle) bilaterally BID. 


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During the screening period, two 90-minute exposures to the CAE will be conducted to ascertain eligibility 
to enter the study at Visit 1 (Day -14 ± 2) and Visit 2 (Day 1). Subjects who qualify after the initial screening 
visit will enter the run-in phase, where they will self-administer vehicle BID for approximately 14 days. Those 
who qualify at Visit 2 (Day 1) will be randomized to receive study drug in a double-masked fashion for 84 
days. Subjects will self-administer drops BID and will complete Daily diary symptom score assessments as 
instructed. The CAE exposure will occur at Visit 1 (Day -14 ± 2), Visit 2 (Day 1), Visit 3 (Day 15 ± 2), Visit 
4 (Day 43 ± 2), and Visit 5 (Day 85 ± 4), with Pre-CAE, during CAE and Post-CAE assessments of ocular 
signs and symptoms. Study drug will be discontinued at Visit 5. Subjects will exit from the study at this visit. 
Study visits will be referred to in all tables and listings as the scheduled visit name and planned study day 
corresponding to the visit to enable reviewers to understand the assessment timing without referring to the 
protocol visit schedule. 
4.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided Appendix 1. 
4.3 
Study Treatments 
IC265 Ophthalmic Solution will be formulated as a sterile, non-preserved solution around pH 6 for topical 
ophthalmic administration and is intended for clinical use. The study drug will be supplied in blow-fill seal 
ampoules, which allow for product administration directly to the eye. Each ampoule will contain a nominal 
volume of 0.27 mL. 
The excipients which will be used to manufacture IC265 Ophthalmic Solution will be standard excipients for 
use in ophthalmic solutions that comply with their respective USP / EP monographs. 
The placebo for IC265 Ophthalmic Solution contains all the same excipients used in the active formulation 
without the API. 
5. Sample Size 
Approximately 80 subjects will be screened to enroll 40 subjects (20 subjects in each group). This is a 
Phase 2 study for which no formal sample size calculation has been performed. The sample size chosen 
was not based on statistical considerations, but is based on historical experience. 
6. Data Preparation 
6.1 
Input Data 
Study data will primarily be recorded on the electronic Case Report Forms (eCRFs) supplied by SDC using 
iMedNet and SDC Capture™.  


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When all prerequisites for database lock have been met, the database will be locked. Following database 
lock, approval will be obtained from the Sponsor to unmask the study. Any changes to the database after 
data have been locked can only be made with the approval of the Sponsor in consultation with SDC.  
Final analysis will be carried out after the following have occurred: 
• 
Database lock has occurred. 
• 
Analysis populations have been determined. 
• 
Randomized treatment codes have been unmasked. 
6.2 
Output Data 
Data from EDC will be transferred to SDC Biostatistics. Data will then be mapped to analysis datasets. Both 
raw and analysis data will be used to create the subject listings, while all tables and figures will be based 
on the analysis data.  
7. Analysis Populations 
7.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population includes all randomized subjects. All efficacy analyses will be 
performed on the ITT Population, and subjects will be analyzed as randomized.  
7.2 
Safety Population 
The Safety Population includes all randomized subjects who receive at least one dose of the investigational 
product. The subjects will be analyzed as treated. All safety analyses will be based on the Safety Population. 
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:  
Study 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 study eye will be the eye with the worst (higher) total corneal fluorescein 
staining, based on the sum of the inferior, superior, and central regions, at baseline (Visit 2) pre-CAE. If the 
total corneal staining is the same in both eyes, then the right eye will be selected as the study eye. 
The non-study eye will be referred to as the fellow eye. Fellow eye safety summaries will also be presented 
as appropriate. Additionally, non-ocular AEs and medical history will be presented at the subject level. 
8.2 
Missing or Inconclusive Data Handling 
8.2.1 
MISSING EFFICACY ASSESSMENTS 
No imputation will be used for efficacy endpoints.  


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8.2.2 
MISSING SAFETY ASSESSMENTS 
No imputation will be used for safety endpoints.  
8.3 
Definition of Baseline 
Baseline measures are defined as the last non-missing measure prior to the initiation of randomized study 
treatment, usually at Visit 2 (Day 1). 
8.4 
Data Analysis Conventions 
All data analysis will be performed by SDC. Statistical programming and analyses will be performed using 
SAS® Version 9.4 or higher. Output will be provided in rich text format (RTF) for tables and portable 
document format (PDF) for tables, listings, and figures using landscape orientation.  
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 counts and 
percentages. All percentages will be rounded to one decimal place (i.e., XX.X%). Differences between 
active treatment and placebo will be calculated as, Active – Placebo, and change from baseline will be 
calculated as, Follow-up Visit – Baseline.  
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit. 
Listings will be presented by subject number, treatment group, visit, time point, and parameter as applicable 
based on all randomized subjects unless otherwise specified.  
8.5 
Adjustments for Multiplicity 
As this is an exploratory study with no primary or secondary endpoints, there will be no multiplicity 
adjustments and all analyses are considered hypothesis-generating. 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized to masked study drug, with subcategories of dosed with the masked study drug and did not 
dose with masked study drug; who were included in the ITT and Safety Populations; and who 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 overall for all subjects. 
Percentages will be calculated using screened subjects as the denominator unless otherwise specified.  
The reasons for premature study discontinuation will be summarized by treatment group and overall for all 
discontinued subjects. Percentages will be calculated using discontinued subjects as the denominator. The 
reasons for study discontinuation that will be summarized include: lost to follow-up, adverse event (AE), 


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protocol violation, administrative reasons, sponsor termination of study, subject request/withdrawal, 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 any deviation will be summarized by treatment group and 
overall for all subjects. The protocol deviations that will be summarized include the following categories: 
non-compliance with informed consent, non-compliance with study inclusion or exclusion criteria, site’s non-
compliance with study treatment, subject’s non-compliance with study treatment, improper protocol 
procedures at site, site’s failure to report serious adverse events (SAE) and/or adverse events (AE), non-
compliance with any scheduled study visit, use of disallowed concomitant medications, subject’s failure to 
follow instructions, and other. A subject listing will be provided that includes the date of the deviation, the 
deviation category, the deviation description, and the classification of whether the deviation was judged to 
be major or minor in a masked review. 
Details of the study randomization, including randomization date, randomized treatment, and actual 
treatment, will also be included within a subject listing. 
10. Demographics and Physical Examination  
10.1 
Demographic Variables 
The demographic variables collected in this study include age, gender assigned at birth (i.e., sex), race, 
ethnicity, and iris color. Subjects who record more than one race will be grouped into a single category 
denoted as Multi-racial in the summary table and will be reported as collected in the subject listing. Iris color 
will be summarized at the subject level. Demographic variables will be summarized for the ITT and Safety 
Populations, separately. 
Age (years) will be summarized, by treatment group and overall for all subjects, using continuous 
descriptive statistics. Age will be reported in years and calculated using the following formula: 
Age (years) = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
The number and percentage of subjects will be presented, by treatment group and overall for all subjects, 
for sex, race, ethnicity, and iris color.  
A subject listing that includes all demographic variables will be provided. 
10.2 
Physical Examination 
Physical examinations of general health, head, eye, ear, nose and throat (HEENT), and other body systems 
will be graded as normal, abnormal not clinically significant (NCS), or abnormal clinically significant (CS).  
A subject listing that includes all physical examination results will be provided. 


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11. Medical History and Concomitant Medications 
Listings of medical history, concomitant medications, and concomitant procedures will be generated 
separately, as well as separately for ocular and non-ocular data. 
11.1 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 
26.1. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment group and overall for all subjects at the subject level by System Organ Class (SOC) and Preferred 
Term (PT) using the Safety Population. Ocular medical history will be similarly summarized at the subject 
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. In the summaries, SOCs are ordered in ascending alphabetical order, and 
PTs within an SOC are sorted by descending frequency for all subjects. 
11.2 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHODrug) Global, B3, September 2023 version and summarized to the therapeutic drug class 
(Anatomical Therapeutic Chemical [ATC] 4 classification) and preferred name. If the ATC 4 classification is 
not provided, then the next highest classification that is provided in the coding dictionary will be used. The 
preferred name will be defined as the active ingredient; if the active ingredient is not provided or includes 
more than two ingredients (e.g., multivitamins), then the drug name will be summarized as the preferred 
name. 
Concomitant medications are defined as those medications listed as having been taken (1) 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. Prior medications are defined as 
those medications that are stopped prior to initiation of study drug administration. 
Concomitant medications will be summarized using the ITT Population. Medications will be tabulated for 
each treatment group using frequencies and percentages. Subjects may have more than one medication 
per ATC text. At each level of subject summarization, a subject will be counted once if he/she reports one 
or more medications. Percentages will be based on the number of subjects in each treatment group. In the 
summaries, ATC Classes and preferred names will be presented in ascending alphabetical order. A listing 
will be provided of prior and concomitant medications. 
11.3 
Concomitant Procedures 
Concomitant procedures will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 26. 1. Concomitant procedures will not be summarized, but a listing will be provided. 


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12. Dosing Compliance and Treatment Exposure 
In addition to the analyses described in the following sections, subject listings will be provided for study 
drug assignment, study drug instillation, and subject daily dosing diary records. 
12.1 
Dosing Compliance 
Dosing compliance (% compliance) will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses as follows: 
Compliance (%) = 
Number of Actual Doses Received 
x 100% 
Number of Expected Doses 
The number of actual doses received will be calculated from the number of used vials recorded in the drug 
accountability eCRF or from the subject diary and in-office instillations. The number of expected doses that 
will be used for calculating compliance will be calculated as:  
Number of Expected Doses = 2 x [(Date of Last Dose - Date of First Dose) + 1] 
for all subjects, regardless of study completion status. 
A categorical dosing compliance variable will also be derived as non-compliant (< 80%), compliant (≥ 80% 
and ≤ 125%), and over compliant (> 125%). 
Dosing compliance (%) will be summarized with continuous descriptive statistics for each treatment group 
using the ITT Population. The compliance category defined above will be summarized with discrete 
summary statistics.  
A subject listing of dosing compliance will also be produced. 
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 Last Dose - Date of First Dose) + 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 First Dose) + 1 
Extent of treatment exposure 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. 


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13. Exploratory Efficacy Analyses 
13.1 
Primary Analysis of Exploratory Efficacy Variables 
All efficacy analyses will be conducted using the ITT Population.  
13.1.1 FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
Fluorescein staining will be conducted at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 5 (pre-
CAE, post-CAE, and pre- to post-CAE) in the following regions: central, superior, inferior, temporal, nasal, 
corneal sum, conjunctival sum, and total eye score.  
The staining will be graded with the Ora Calibra® Corneal and Conjunctival Staining Scale, which is as 
follows: 0 = None, 1 = Trace, 2 = Mild, 3 = Moderate, 4 = Severe. Half (0.5) increments may be used. 
The fluorescein staining results for the study eye will be summarized using continuous descriptive statistics 
by visit and eye for each treatment group and all randomized subjects. A subject listing of fluorescein 
staining results will also be produced. 
13.1.2 OCULAR DISCOMFORT AND DRY EYE SYMPTOMS 
Ocular discomfort scores will be subjectively graded by the subjects according to the following scale, rating 
each eye separately: 0 = No discomfort, 1 = Intermittent awareness, 2 = Constant awareness, 3 = 
Intermittent discomfort, 4 = Constant discomfort. Additionally, subjects will rate the severity of each of the 
following symptoms, with regard to how both their eyes feel, in general – overall ocular discomfort, burning, 
dryness, grittiness and stinging according to the following 6-point (0 to 5) scale where 0 = none and 5 = 
worst. Both ocular discomfort and dry eye symptoms will be assessed at each visit. 
Ocular discomfort and dry eye symptoms for the study eye will be summarized using continuous descriptive 
statistics by visit for each treatment group and all randomized subjects. A subject listing of ocular discomfort 
and 4-symptom questionnaire results will also be produced. 
13.1.3 LISSAMINE GREEN STAINING (ORA CALIBRA® SCALE) 
Lissamine green staining will be conducted at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 
5 (pre-CAE, post-CAE, and pre- to post-CAE) in the following regions: central, superior, inferior, temporal, 
nasal, corneal sum, conjunctival sum, and total eye score.  
The staining will be graded with the Ora Calibra® Corneal and Conjunctival Staining Scale, which is as 
follows: 0 = None, 1 = Trace, 2 = Mild, 3 = Moderate, 4 = Severe. Half (0.5) increments may be used. 
The lissamine staining results for the study eye will be summarized using continuous descriptive statistics 
by visit and eye for each treatment group and all randomized subjects. A subject listing of lissamine staining 
results will also be produced. 


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13.1.4 TEAR FILM BREAK-UP TIME 
TFBUT will be measured in seconds using a stopwatch and a digital image recording system for the right 
eye followed by the left eye at Visits 3, 4 (pre-CAE, post-CAE, and pre- to post-CAE), and 5 (pre-CAE, post-
CAE, and pre- to post- CAE). For each eye, 2 measurements will be taken and averaged unless the 2 
measurements are > 2 seconds apart and are each < 10 seconds, in which case, a third measurement 
would be taken and the 2 closest of the 3 would be averaged. 
The TFBUT values for the study eye will be summarized using continuous descriptive statistics by visit and 
eye for each treatment group and for all randomized subjects. A subject listing of TFBUT will also be 
produced. 
13.1.5 CONJUNCTIVAL REDNESS 
The Ora Calibra® Conjunctival Redness Scale for Dry Eye will be performed at Visits 2 (pre-CAE), 3, 4 (pre-
CAE, post-CAE, and pre- to post-CAE), and 5 (pre-CAE, post-CAE, and pre- to post-CAE). The scale is as 
follows: 0 = None, 1 = Trace, 2 = Mild, 3 = Moderate, 4 = Severe. Half (0.5) increments may be used. 
The scale values for the study eye will be summarized using continuous descriptive statistics by visit and 
eye for each treatment group and all randomized subjects. A subject listing of conjunctival redness results 
will also be produced. 
13.1.6 OCULAR SURFACE DISEASE INDEX (OSDI) 
Ocular Surface Disease Index (OSDI©) includes the following questions: 
1. Eyes that are sensitive to light? 
2. Eyes that feel gritty? 
3. Painful or sore eyes? 
4. Blurred vision? 
5. Poor vision? 
6. Reading? 
7. Driving at night? 
8. Working with a computer or bank machine (ATM)? 
9. Watching TV? 
10. Windy conditions? 
11. Places or areas with low humidity (very dry)? 
12. Areas that are air conditioned? 
OSDI© will be collected for both eyes at Visits 1, 2, 3, 4 and 5 (pre-CAE). The 5-unit scale for responses to 
the OSDI© is given by the following: 0 = None of the time, 1 = Some of the time, 2 = Half of the time, 3 = 
Most of the time, and 4 = All of the time. The total OSDI© score is calculated by the following: 


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OSDI© = 
(Sum of Scores) x 25 
# of Questions Answered 
Note that the number of questions answered in the denominator should exclude those questions with a 
response of “N/A.” Continuous descriptive statistics, including 95% CIs, as well as changes from baseline 
will be summarized by treatment group as well as between treatment groups. All categorical safety 
assessments will be summarized by treatment and time point (as applicable) using discrete summary 
statistics. A subject listing of OSDI© results will also be produced. 
13.1.7 UNANESTHETIZED SCHIRMER’S TEST 
Subjects’ will have the length of the moistened area from the sterile Tear Flo Schirmer strip assessed in 
each eye at Visits 3, 4, and 5. The Schirmer’s test strip will be placed in the lower temporal lid margin of 
each eye. After 5 minutes, the test strip will be removed, and the length of the moistened area will be 
recorded in millimeters (mm) for each eye. 
The length values for the study eye will be summarized using continuous descriptive statistics by visit and 
eye for each treatment group and for all actively treated subjects. A subject listing of Schirmer’s test results 
will also be produced.  
13.1.8 OCULAR DISCOMFORT DURING CAE 
Ocular discomfort scores will be subjectively graded by the subjects according to the following Ora Calibra® 
Ocular Discomfort Scale for Dry Eye, rating each eye separately, where: 0 = No discomfort, 1 = Intermittent 
awareness, 2 = Constant awareness, 3 = Intermittent discomfort, 4 = Constant discomfort. The procedure 
will occur during the 90 minute CAE exposure, starting at time 0 and then every 5 minutes thereafter. 
Ocular discomfort scores at Visits 4 and 5 for the study eye will be summarized using continuous descriptive 
statistics by visit and eye for each treatment group and for all actively treated subjects. A subject listing of 
ocular discomfort scores will also be produced.  
13.1.9 DAILY DIARY SYMPTOM SCORE 
Subjects will be asked to complete a dosing diary daily between Visit 1 and Visit 5. The diary symptom 
scores will be summarized using continuous descriptive statistics for each treatment group and for all 
actively treated subjects, for the following windows: Day -14 to Day 0, Day 1 to Day 7, Day 8 to Day 14, 
Day 15 to Day 28, Day 29 to Day 42, Day 43 to Day 63, Day 64 to Day 85. A subject listing will be provided 
for daily dosing diary records. 
13.2 
Sensitivity Analysis of Efficacy Variable(s) 
Sensitivity analyses will not be conducted for efficacy variables.  


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14. Safety Analyses 
All safety analyses will be conducted using the Safety Population. 
14.1 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or worsens on or after 
the first dose of study drug administration. Only TEAEs will be summarized, however all AEs collected in 
the eCRF will be presented in data listings. All AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 26.1.  
An overall summary will be presented that includes the number of events and the number and percentage 
of subjects who experienced at least one TEAE, by treatment group. This summary will also include 
breakdowns of TEAEs further categorized as ocular (study eye and fellow eye separately) or non-ocular, 
treatment-related TEAEs, treatment-emergent serious adverse events (TE-SAEs), TEAEs leading to early 
treatment discontinuation, TEAEs leading to death, and TEAEs by maximum severity. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE by treatment group and classified by the MedDRA SOC and PT. Ocular 
and non-ocular TEAEs will be summarized separately. If a subject reports multiple TEAEs to the same SOC 
or multiple PTs within the same SOC, the subject will be counted only once within that SOC or PT. In the 
summaries, SOCs will be listed in ascending alphabetical order; PTs will be listed in order of descending 
frequency for all subjects within each SOC.  
Separate summaries by SOC and PT will be provided for the following categories of AEs:  
• 
Ocular TEAEs  
• 
Non-ocular TEAEs  
• 
Treatment-related ocular TEAEs 
• 
Treatment-related non-ocular TEAEs 
• 
TE-SAEs 
Summaries of TEAEs by maximum severity will be presented for ocular AEs and non-ocular TEAEs 
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 SOC or PT within an SOC, the subject will be counted once under the 
maximum severity. 
All AEs will be presented in a subject listing. In addition, SAEs and AEs leading to study treatment 
discontinuation will be listed separately.  


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14.2 
Visual Acuity  
The logarithm of the minimum angle of resolution (logMAR) visual acuity is assessed at each visit using an 
Early Treatment Diabetic Retinography Study (ETDRS) chart. Subjects should use their most recent 
correction to attain their visual acuity (VA). 
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 and for all actively 
treated subjects. A subject listing of visual acuity will also be produced. This listing will include a variable 
that indicates if a subject had a visual acuity change from baseline of ≥0.2 on the logMAR scale. 
14.3 
Slit-Lamp Biomicroscopy 
A slit-lamp biomicroscopy examination of the cornea, conjunctiva, anterior chamber, iris, lens, and eyelid 
will be performed at each visit. The results will be graded as normal, abnormal not clinically significant 
(NCS), or abnormal clinically significant (CS). 
The results will be summarized using counts and percentages for each treatment group and for all actively 
treated subjects 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. A subject listing of the slit-lamp 
biomicroscopy parameters will also be produced. 
14.4 
Undilated Fundoscopy 
An undilated fundoscopy examination of the vitreous, retina, macula, choroid and optic nerve will be 
performed at each visit. The results will be graded as normal, abnormal NCS, or abnormal CS.  
The results will be summarized using counts and percentages for each treatment group and for all actively 
treated subjects 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 undilated fundoscopy 
parameters will also be provided comparing each follow-up visit to baseline. A subject listing of the undilated 
fundoscopy parameters will also be produced. 
14.5 
Intraocular Pressure 
Subjects’ IOP will be assessed by non-contact tonometry in each eye at each visit. Results will be taken 
from a single measurement and will be recorded in millimeters of Mercury (mmHg). 
The IOP values and changes from baseline for each eye (study eye and fellow eye) will be summarized 
using continuous descriptive statistics by visit and eye for each treatment group and for all actively treated 
subjects. A subject listing of IOP will also be produced. This listing will include identifiers which indicates if 
a subject had an IOP increase from baseline of ≥6 or ≥10 mmHg. 


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14.6 
Drop Comfort Scale Assessment 
Subjects’ drop comfort will be assessed for each eye at Visits 2, 3, and 4 using the Ora Calibra® Drop 
Comfort Scale, where 0 indicates Very Comfortable and 10 indicates Very Uncomfortable. 
The scale values for each eye (study eye and fellow eye) will be summarized using continuous descriptive 
statistics by visit and eye for each treatment group and all randomized subjects. A subject listing of drop 
comfort results will also be produced. 
15. Other Data 
15.1 
Physical Examination 
Physical examinations of general health, head, eye, ear, nose and throat (HEENT), and other body systems 
will be graded as normal, abnormal not clinically significant (NCS), or abnormal clinically significant (CS).  
A subject listing that includes all physical examination results will be provided. 
15.2 
Visual Analog Scale 
A VAS instrument measures a characteristic that spans a continuum, cannot be precisely or optimally 
measured by, or would lack sensitivity in distinguishing subtle changes on an ordinal scale. VAS will be 
administered to assess the subject’s experience of ocular discomfort (unrelated to study drug instillation), 
where higher score indicates greater discomfort.  
A subject listing that includes all VAS results will be provided. 
16. Interim Analyses 
There will be no interim analyses in this study. To note, the study was terminated early on 16NOV2023. 
17. Changes from Protocol-Stated Analyses 
Changes from the protocol-stated analyses, due to early termination of the study on 16NOV2023, include 
the following: 
• 
Per Protocol population will not be determined.  
• 
No imputation will be used for efficacy or safety endpoints. Specifically, the ITT population will not 
be analyzed using the Last Observation Carried Forward (LOCF) imputation method and multiple 
imputation. 
• 
Sensitivity analyses will not be conducted as the PP population has been removed and no 
imputation will be used.  
• 
Statistical testing will not be conducted. Descriptive statistics will be utilized for the efficacy and 
safety endpoints. 


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18. References 
1. ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials E9. International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. 05 
February 1998. 
2. ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports E3. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use. 30 November 1995. 
19. Revision History 
Documentation of revision to the SAP will commence after approval of the final version 1.0. 
20. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  
Table Number 
Title 
Population 
14.1.1 
Subject Disposition 
All Screened 
Subjects 
14.1.2 
Protocol Deviations 
Intent-to-Treat 
Population 
14.1.2.1 
Demographics 
Intent-to-Treat 
Population 
14.1.2.2 
Demographics 
Safety Population 
14.1.3.1 
Ocular Medical History 
Safety Population 
14.1.3.2 
Non-Ocular Medical History 
Safety Population 
14.1.4.1 
Ocular Concomitant Medications 
Intent-to-Treat 
Population 
14.1.4.2 
Non-Ocular Concomitant Medications 
Intent-to-Treat 
Population 
14.1.5.1 
Study Drug Compliance 
Intent-to-Treat 
Population 
14.1.5.2 
Overall Study Drug Exposure 
Safety Population 
14.2.1.1 
Ora Calibra Corneal and Conjunctival Fluorescein Staining 
in Study Eye by Visit 
Intent-to-Treat 
Population 
14.2.1.2 
Ora Calibra Ocular Discomfort & 4-Symptoms 
Questionnaire in Study Eye by Visit 
Intent-to-Treat 
Population 


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Table Number 
Title 
Population 
14.2.1.3 
Ora Calibra Ocular Discomfort Scale during the CAE 
in Study Eye by Visit 
Intent-to-Treat 
Population 
14.2.1.4 
Ora Calibra Corneal and Conjunctival Lissamine Green 
Staining in Study Eye by Visit 
Intent-to-Treat 
Population 
14.2.1.5 
Tear Film Break-Up Time (TFBUT) in Study Eye by Visit 
Intent-to-Treat 
Population 
14.2.1.6 
Ora Calibra Conjunctival Redness in Study Eye by 
Visit 
Intent-to-Treat 
Population 
14.2.1.7 
Ocular Surface Disease Index (OSDI) by Visit 
Intent-to-Treat 
Population 
14.2.1.8 
Unanesthetized Schirmer’s Test in Study Eye by Visit 
Intent-to-Treat 
Population 
14.2.1.9 
Daily Diary Symptom Score 
Intent-to-Treat 
Population 
14.3.1.1 
Overall Summary of Adverse Events 
Safety Population 
14.3.1.2 
Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Population 
14.3.1.3 
Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Population 
14.3.1.4 
Ocular Treatment-Related Treatment-Emergent 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Population 
14.3.1.5 
Non-Ocular Treatment-Related Treatment-Emergent 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Population 
14.3.1.6 
Serious Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Population 
14.3.2 
Visual Acuity (logMAR) by Visit 
Safety Population 
14.3.3.1 
Slit Lamp Biomicroscopy Results by Visit 
Safety Population 
14.3.3.2 
Shifts in Slit Lamp Biomicroscopy from Baseline to Each 
Post-Baseline Visit 
Safety Population 
14.3.4.1 
Undilated Fundus Exam Results by Visit 
Safety Population 
14.3.4.2 
Shifts in Undilated Fundus Exam Results from Baseline to 
Each Post-Baseline Visit 
Safety Population 


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Table Number 
Title 
Population 
14.3.5 
Intraocular Pressure by Visit 
Safety Population 
14.3.6 
Ora Calibra Drop Comfort Scale by Visit 
Safety Population 
21. Listings 
Listings that will be included in the topline delivery are shown in boldface font.  
Listing Number 
Title 
Population 
16.1.7 
Randomization Schedule 
All Randomized 
Subjects 
16.2.1.1 
Subject Dispositions 
All Randomized 
Subjects 
16.2.1.2 
Inclusion/Exclusion Criteria 
All Screened Subjects 
16.2.2 
Protocol Deviations 
All Randomized 
Subjects 
16.2.4.1 
Demographics 
All Randomized 
Subjects 
16.2.4.2 
Medical History 
All Randomized 
Subjects 
16.2.4.3 
Prior and Concomitant Medications 
All Randomized 
Subjects 
16.2.4.4 
Concomitant Procedures 
All Randomized 
Subjects 
16.2.5.1 
Study Drug Assignment and Accountability 
All Randomized 
Subjects 
16.2.5.2 
Study Drug Exposure and Dosing Compliance 
All Randomized 
Subjects 
16.2.5.3 
Study Drug Instillation 
All Randomized 
Subjects 
16.2.6.1 
Ora Calibra Corneal and Conjunctival Fluorescein Staining 
All Randomized 
Subjects 
16.2.6.2 
Ora Calibra Ocular Discomfort & 4-Symptom 
Questionnaire 
All Randomized 
Subjects 
16.2.6.3 
Ora Calibra Ocular Discomfort Scale during the CAE 
All Randomized 
Subjects 


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Listing Number 
Title 
Population 
16.2.6.4 
Ora Calibra Corneal and Conjunctival Lissamine Green 
Staining 
All Randomized 
Subjects 
16.2.6.5 
Tear Film Break-Up Time (TFBUT) 
All Randomized 
Subjects 
16.2.6.6 
Ora Calibra Conjunctival Redness 
All Randomized 
Subjects 
16.2.6.7 
Ocular Surface Disease Index (OSDI) 
All Randomized 
Subjects 
16.2.6.8 
Unanesthetized Schirmer’s Test 
All Randomized 
Subjects 
16.2.6.9 
Daily Diary Symptom Score 
All Randomized 
Subjects 
16.2.7.1 
All Adverse Events 
All Randomized 
Subjects 
16.2.7.2 
Serious Adverse Events  
All Randomized 
Subjects 
16.2.7.3 
Adverse Events Leading to Study Treatment 
Discontinuation 
All Randomized 
Subjects 
16.2.8.1 
Urine Pregnancy Test Results 
All Randomized 
Female Subjects of 
Childbearing Potential 
16.2.9.1 
Visual Acuity (VA) 
All Randomized 
Subjects 
16.2.9.2 
Slit-Lamp Biomicroscopy 
All Randomized 
Subjects 
16.2.9.3 
Undilated Fundoscopy 
All Randomized 
Subjects 
16.2.9.4 
Intraocular Pressure (IOP) 
All Randomized 
Subjects 
16.2.9.5 
Ora Calibra Drop Comfort Scale 
All Randomized 
Subjects 
16.2.9.6 
Ora Calibra Ocular Discomfort Scale outside the CAE 
All Randomized 
Subjects 
16.2.9.7 
Physical Examination 
All Randomized 
Subjects 


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Listing Number 
Title 
Population 
16.2.9.8 
Visual Analog Scale (VAS) 
All Randomized 
Subjects 
22. Figures 
Figure Number 
Title 
Population 
 
 
 
 
 
 


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23. Appendices 
23.1 
Appendix 1: Schedule of Visits and Measurements 
 
 
 


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