Clinical trial NCT05241470
Conditions: Dry Eye Disease
Sponsor: Stuart Therapeutics, Inc.
Start date: 2021-05-17; Completion date: 2021-10-11
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to compare the safety and efficacy of two different concentrations of ST-100 Ophthalmic Solution to placebo (vehicle) for the treatment of the signs and symptoms of dry eye.

Detailed description:
This is a Phase 2, multi-center, double-masked, randomized, placebo-controlled clinical study. Subjects will be randomized to one of the following treatment arms at Visit 2 (Day 1):

* Low dose ST-100 Ophthalmic Solution: 1 drop twice daily (BID) in each eye
* High dose ST-100 Ophthalmic Solution: 1 drop BID in each eye
* Placebo Ophthalmic Solution (Vehicle): 1 drop BID in each eye

Approximately 150 subjects will be randomly assigned to one of the three groups (1:1:1) to receive either ST-100 Ophthalmic Solution or placebo solution as topical ophthalmic drops administered bilaterally BID for 4 weeks. Subjects, Sponsor, Contract Research Organization (CRO), and site personnel will be masked to treatment assignment.

The clinical hypotheses for this study is that low dose and high dose ST-100 Ophthalmic Solution twice daily (BID) is superior to its vehicle (BID) for the primary endpoints of signs and symptoms of dry eye.

Arms: arm 1: Low Dose ST100-001 Ophthalmic solution, 20mcg/ml arm 2: High Dose ST100-001 Ophthalmic Solution, 50mcg/ml arm 3: Placebo Ophthalmic Solution (vehicle)
Interventions: intervention 1: ST-100 Ophthalmic Solution intervention 2: Placebo Ophthalmic Solution
Intervention descriptions: intervention 1: One drop in each eye twice a day intervention 2: One drop in each eye twice a day

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol: Study ST100-001 
Protocol Title: 
A Phase 2 Multi-Center, Randomized, Double Masked, 
Placebo Controlled Study to Assess the Safety and 
Efficacy of ST-100 Ophthalmic Solution in Subjects 
Diagnosed with Dry Eye Disease 
Protocol Number: 
ST100-001 
Study Phase: 
2 
Investigational Product Name: 
ST-100 Ophthalmic Solution 
IND Number: 
143015 
Indication: 
Dry Eye Disease 
Investigators: 
Multi-Center 
Sponsor: 
Stuart Therapeutics, Inc. 
411 SE Osceola St., Suite 203 
Stuart, FL 34994 USA 
 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 USA 
IRB/IEC: 
 
Original Protocol:  
Protocol Amendment 1: 
March 15, 2021 
May 21, 2021 
 
 
Confidentiality Statement 
 
This protocol contains confidential, proprietary information of Ora, Inc. Further dissemination, 
distribution or copying of this protocol or its contents is strictly prohibited. 
 
 
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Protocol 
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TABLE OF CONTENTS 
Synopsis ......................................................................................................................3 
Table of Contents ........................................................................................................8 
List of Abbreviations .........................................................................................................12 
Introduction ...............................................................................................................13 
Study Objectives .......................................................................................................14 
Clinical Hypothesis ...................................................................................................14 
Overall Study Design ................................................................................................15 
Study Population .......................................................................................................16 
Number of Subjects (approximate) ................................................................16 
Study Population Characteristics ....................................................................16 
Inclusion Criteria ............................................................................................17 
Exclusion Criteria ...........................................................................................17 
Withdrawal Criteria (if applicable) ................................................................19 
Study Parameters ......................................................................................................19 
Efficacy Endpoints .........................................................................................19 
6.1.1 
Primary Efficacy Endpoints ..............................................................19 
6.1.2 
Secondary Efficacy Endpoints ..........................................................19 
Safety Measures .............................................................................................20 
Study materials..........................................................................................................20 
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. .........................................20 
7.1.3 
Instructions for Use and Administration ...........................................21 
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 
Other Study Supplies ......................................................................................21 
Study Methods and Procedures .................................................................................22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
Concurrent Therapies .....................................................................................22 
8.2.1 
Prohibited Medications/Treatments ..................................................22 
8.2.2 
Escape Medications ..........................................................................23 
8.2.3 
Special Diet or Activities ..................................................................23 
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 –7 ± 1 – CAE® Screening .............................................23 
8.3.3 
Visit 2: Day 1 – CAE® Confirmation and Baseline ..........................24 
8.3.4 
Visit 3: Day 2 ± 2 hours, 24 h recovery post-CAE® .........................26 
8.3.5 
Visit 4: Day 4 ± 2 hours, 72 h recovery post-CAE® .........................26 
8.3.6 
Visit 5: Day 8 ± 1, 1-Week CAE® Follow-Up..................................27 
8.3.7 
Visit 6: Day 15 ± 1, 2-Week CAE® Follow-Up................................28 
8.3.8 
Visit 7: Day 29 ± 2, 4-Week CAE® Follow-Up................................29 
Schedule of Visits, Measurements and Dosing ..............................................30 
8.4.1 
Scheduled Visits................................................................................30 
8.4.2 
Unscheduled Visits ...........................................................................30 
Compliance with Protocol ..............................................................................31 
Subject Disposition .........................................................................................31 
8.6.1 
Completed Subjects ..........................................................................31 
8.6.2 
Discontinued Subjects .......................................................................31 
Study Termination ..........................................................................................31 
Study Duration ...............................................................................................32 
Monitoring and Quality Assurance ................................................................32 
Adverse Events .........................................................................................................32 
Adverse Event (AE) .......................................................................................32 
9.1.1 
Severity .............................................................................................33 
 
 
 
 
 
 
 
 
 
 
 
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9.1.2 
Relationship to Investigational Product ............................................33 
9.1.3 
Expectedness .....................................................................................34 
Serious Adverse Events ..................................................................................34 
Procedures for Reporting Serious Adverse Events ........................................35 
9.3.1 
Reporting a Serious Unexpected Suspected Adverse Reaction ........35 
9.3.2 
Reporting a Serious Adverse Event ..................................................35 
Procedures for Unmasking (if applicable) ......................................................35 
Type and Duration of the Follow-up of Subjects after Adverse Events ........36 
Statistical Hypotheses and Methods of Analysis ......................................................36 
Analysis Populations ......................................................................................36 
Statistical Hypotheses .....................................................................................37 
Sample Size ....................................................................................................37 
Statistical Analysis .........................................................................................38 
10.4.1 General Considerations .....................................................................38 
10.4.2 Unit of Analysis ................................................................................38 
10.4.3 Missing Data .....................................................................................38 
10.4.4 Multiplicity Consideration ................................................................39 
10.4.5 Efficacy Analyses .............................................................................39 
10.4.6 Safety Variables ................................................................................41 
10.4.7 Interim Analyses ...............................................................................41 
Compliance with Good Clinical PractiCes, Ethical Considerations, and Administrative 
Issues .........................................................................................................................42 
Protection of Human Subjects ........................................................................42 
11.1.1 Subject Informed Consent.................................................................42 
11.1.2 Institutional Review Board (IRB) Approval .....................................42 
Ethical Conduct of the Study ..........................................................................42 
Subject Confidentiality ...................................................................................42 
Documentation ...............................................................................................43 
11.4.1 Retention of Documentation .............................................................43 
Recording of Data on Source Documents and Case Reports Forms (CRFs) .43 
Publications ....................................................................................................43 
References .................................................................................................................44 
Appendices ................................................................................................................45 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1: Schedule Of Visits And Measurements .....................................45 
Appendix 2: Examination Procedures, Tests, & Evaluations ........................47 
Appendix 3: Protocol Amendment Summary ................................................62 
Appendix 4: Sponsor And Ora Approvals .....................................................67 
Appendix 5: Investigator’s Signature .............................................................68 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
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 
ECM 
Extracellular Matrix 
eCRF 
electronic Case Report Form 
EP 
European Pharmacopoeia 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
U.S. 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 
LPI 
Laser Peripheral Iridotomy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
Matrix Metalloproteinase 
NCS 
Not Clinically Significant 
OD 
Right Eye 
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 
USP 
United States Pharmacopeia 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
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 INTRODUCTION 
Dry eye disease (DED) is a prevalent chronic eye condition affecting between 5% and 34% of 
the population worldwide. More than 16 million Americans suffer from DED, including 
approximately 1 million to 4 million between 65 to 84 years of age (Fiscella 2011,          
Messmer 2015). Furthermore, the age of onset is decreasing rapidly due to the widespread 
increase in electronic “screen time” such that teenagers are now more frequently showing signs 
and symptoms of DED. Symptoms include severe ocular burning, discomfort, pain, and in more 
severe cases compromised visual function, including symptomatic blurred vision. These 
symptoms are associated with tear film hyperosmolarity and instability, inflammation, and 
wounding of the corneal epithelium and the collagen substrate (Bowman’s layer) that is part of 
the extracellular matrix (ECM) and to which the epithelium adheres and renews. As is now 
recognized, even the early stages of DED tissue damage penetrates well beyond the surface 
epithelial layer and involves the ECM, including disruption of the collagen that is contained in 
Bowman’s layer and the underlying corneal stroma (Shetty, Deshpande et al. 2016).  
Epithelial cell apoptosis incites the release of inflammatory cytokines and proteinases, most 
notably IL-6, IL-8 and matrix metalloproteinases (MMPs). In the eye, MMP-9 partially digests 
collagen via its collagenase activity leading to structural and functional disruptions in the 
collagen matrix underlying the corneal epithelium (Baratta et.al., in press). Topical anti-
inflammatory therapies (e.g., Restasis®, Xiidra®, Cequa™) have been used to interrupt this 
process, but they act extremely slowly. Full restoration of corneal homeostasis requires a fully 
regenerated surface epithelium, which first requires the repair of the collagen substrate. Such 
repaired collagen then shows the tightly structured and organized fibrillar pattern characteristic 
of native type I collagen, leading to a resumption of the functional activities of collagen in 
modulating structural integrity of the ocular ECM and in mediating certain signal transduction 
activities. This restoration of collagen and ECM homeostasis in turn promotes the rapid 
regeneration of the corneal epithelium (see, e.g., Kivanany et al., 2018; Hapach et al., 2015).  
Disruptions in the epithelial basement membrane, which comprises several collagen types, are 
also a critical part of ocular surface pathology. Disruption in the basement membrane collagen 
network leads to adverse effects on the integrity of Bowman’s membrane and allows 
inflammatory cytokines to pass through, increasing inflammatory cell infiltration in the area of 
the wound (Shetty, Deshpande et al. 2016). In addition to these anatomical and physiological 
changes, certain changes in cellular signaling activities occur as well. This is both a hallmark and 
a cause of DED (see, e.g., Baratta et al. (2021, in press)).  
No topical therapeutic to date fully addresses the collagenase-mediated damage to the collagen-
containing ocular surface tissue that is associated with DED. Topical but indirect therapies for 
treating tissue damage in DED are available (e.g., amniotic membrane implants, soft contact 
lenses, and topical anti-inflammatories such as those described above) but these indirect topical 
treatments and anti-inflammatories only allow the body to heal collagen secondarily, slowly and 
quite unpredictably. Thus, there remains an urgent and unmet medical need for a direct, rapidly 
acting and therefore more efficacious treatment option with favorable safety and comfort profiles 
that also will promote actual repair of the ocular tissue damage that is a hallmark of DED. 
ST-100, a formulation comprising a synthetic collagen mimetic peptide, is being developed to 
topically treat the signs and symptoms of DED.  
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ST-100 is believed to rapidly repair damaged collagen via intercalation into the disrupted 
collagen and reformation of the native collagen I triple helix. 
Currently, the most common prescription therapeutics for DED are topical anti-inflammatories 
such as Xiidra®, Restasis® and Cequa™. These traditional therapies, however, do not directly 
treat a major underlying cause and effect of DED – damage to the ocular surface tissue and 
specifically to the collagen in the ECM within and underlying the corneal epithelium. The 
Sponsor has therefore sought to identify and evaluate potential therapeutic formulations which 
directly repair ocular surface tissue damage which would provide a more rapid and enduring 
relief of symptoms compared to traditional therapeutic approaches. To date such a therapeutic 
has not been available. ST-100 addresses this gap as it is thought to rapidly repair damaged 
collagen via intercalation into damaged collagen triple helices, thereby repairing the ocular 
surface damage that underlies the signs and symptoms associated with DED. It is anticipated that 
by healing the underlying collagen matrix of corneal tissues, ST-100 will also reduce the 
necessity for long-term use of traditional anti-inflammatory regimens. 
In a non-clinical, proof-of-concept study in mice, application of ST-100 to the wounded eyes of 
mice was shown to induce significant recovery of the corneal epithelium, stromal matrix and 
Bowman’s layer following lamellar keratectomy compared to phosphate-buffered saline negative 
controls. Together with corresponding data obtained using in vitro models of the corneal 
epithelium, these results encouraged the Sponsor to examine the potential for use of ST-100 as a 
topical, rapidly acting therapeutic for DED in humans. 
 STUDY OBJECTIVES 
The objective of this study is to compare the safety and efficacy of two different concentrations 
of ST-100 Ophthalmic Solution to placebo for the treatment of the signs and symptoms of dry 
eye. 
 CLINICAL HYPOTHESIS 
The clinical hypotheses for this study is that low dose and high dose ST-100 Ophthalmic 
Solution twice daily (BID) is superior to its vehicle (BID) for the primary endpoints of signs and 
symptoms of dry eye, as follows:  
•
Sign: Pre-Controlled Adverse Environment (CAE®) total corneal fluorescein staining
score on the Ora Calibra® scale, measured by 
•
Symptom: Pre-CAE® ocular discomfort scale on the Ora Calibra® Ocular Discomfort
scale, measured by 
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4. Have used any eye drops within 2 hours of Visit 1;
5. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within the last 12
months;
6. Have used Restasis, Xiidra, or Cequa ophthalmic solutions within 45 days of Visit 1;
7. Have any planned ocular and/or lid surgeries over the study period or any ocular surgery
within the last 6 months;
8. Have used, are using or anticipate using permanent or temporary punctal plugs during the
study within 30 days of Visit 1;
9. Be currently taking any topical ophthalmic prescription (including medications for
glaucoma) or over-the-counter solutions, artificial tears, gels or scrubs, or using a moisture
chamber and cannot discontinue these medications for the duration of the trial (excluding
medications allowed for the conduct of the study);
10. Be currently taking or have taken Omega-3 supplements within the last 3 months;
11. Have corrected visual acuity (VA) greater than or equal to Logarithm of the Minimum Angle
of Resolution (logMAR) 
 as assessed by Early Treatment of Diabetic Retinopathy Study
(ETDRS) scale in both eyes at Visit 1;
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 is
permanently sterilized (e.g. has had a hysterectomy or tubal ligation), or is post-menopausal
(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 – oral, implantable, injectable, or
transdermal contraceptives; mechanical – spermicide in conjunction with a barrier such as a
diaphragm or condom; intrauterine device; or surgical sterilization of partner. For non-
sexually active females, abstinence may be regarded as an adequate method of birth control;
however, if the subject becomes 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 allergy and/or sensitivity to the test article or its components;
16. Have a condition or be in a situation that the investigator feels may put the subject at
significant risk, may confound the study results, or may interfere significantly with the
subject’s participation in the study;
17. Be currently enrolled in an investigational drug or device study or have used an
investigational drug or device within 30 days of Visit 1;
18. Be currently using any medication known to cause ocular drying that is not used on a stable
dosing regimen for at least 30 days prior to Visit 1;
19. Have a known history of meibomian gland procedures (e.g., LipiFlow, LPI, probing, etc.)
within 6 months of study enrollment;
20. Be unable or unwilling to follow instructions, including participation in all study assessments
and visits.
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• Ocular Discomfort Scale outside of the CAE® at Visits 3, 4, 5, 6, and 7 (pre-CAE®, post-
CAE®, and pre- to post-CAE®) 
• Four symptom questionnaire at Visits 3, 4, 5, 6, and 7 (pre-CAE®, post-CAE®, and pre- 
to post-CAE®) 
 
SAFETY MEASURES 
The safety measures being evaluated are: 
• 
Visual acuity 
• 
Slit-lamp evaluation 
• 
Adverse event query 
• 
Intraocular pressure 
• 
Undilated fundoscopy  
 STUDY MATERIALS 
 
STUDY TREATMENTS 
7.1.1 Study Drug Formulation 
All arms will be double-masked. Subjects will be randomized 1:1:1 into: 
• High dose ST-100; BID 
• Low dose ST-100; BID 
• Placebo Ophthalmic Solution (Vehicle); BID  
ST-100 Ophthalmic Solution will be formulated as a sterile solution at 
 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 0.25 mL.  
The excipients which will be used to manufacture ST-100 Ophthalmic Solution will be standard 
excipients for use in ophthalmic solutions that comply with their respective USP / EP 
monographs. 
The placebo for ST-100 Ophthalmic Solution contains all the same excipients used in the active 
formulation without the peptide. 
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 4 weeks. 
 
 
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7.1.3 Instructions for Use and Administration 
• Subjects will receive placebo ophthalmic solution at Visit 1, and assigned study drug kit 
at Visit 2, 5 and 6. 
• Subjects who are randomized must administer study drug in each eye BID. At Visit 2 and 
6, subjects will self-administer one dose of study drug in office. Subjects should NOT 
self-adminster study drug at home on the morning of their scheduled Visit 2 and Visit 6. 
 
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 ST-100 will be blow-fill-seal ampules with a fill volume of 
. The 
secondary packaging is a foil pouch that contains three ampules in each pouch. Each clinical kit 
will contain 6 pouches, for a total of 18 ampules per kit. 
Run-in Period 
For the run-in period, each subject will receive 1 kit.  
Treatment Period 
BID Dosing: For the treatment period, each subject will receive 1 kit at Visit 2, 1 kit at Visit 5 
and 2 kits at Visit 6.  
7.2.2 Storage of Investigational Product 
Ampoules must be stored at 2 to 8°C until the time of use. The ampoules are to be kept 
refrigerated at the study site and by the subject at their home.  Any material remaining in the 
ampoule after use should be discarded. ST-100 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. 
 
OTHER STUDY SUPPLIES 
Other study supplies include Schirmer’s test strips, sodium fluorescein, lissamine green, Fluress, 
Tropicamide, and daily diary. 
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 STUDY METHODS AND PROCEDURES 
 
SUBJECT ENTRY PROCEDURES 
8.1.1 Overview 
Subjects as defined by the criteria in Section 5.3 and Section 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 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. The Interactive Web Response System (IWRS) will 
be used to assign all randomization numbers. 
Randomization and kit numbers will be assigned automatically to each subject as they are 
entered into the 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. 
 
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).  
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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. 
 
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 –7 ± 1 – 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  
• 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 
• Adverse Event (AE) Query 
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• 90-minute CAE® exposure 
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 
• 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 in each eye until Visit 2. Subjects will be 
instructed NOT to instill run-in on the morning of their next scheduled study visit (Visit 
2).  
• AE Query 
• 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 
• Confirm subject has NOT administered their morning study drug dose at home 
• Medical and Medication History Update 
• Review of Inclusion/Exclusion Criteria 
• 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  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
• AE Query 
• At least 15 minute wait between Schirmer’s test and CAE® exposure 
• 90-minute CAE® exposure; 
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: All subjects having a positive response and 
meeting all other screening eligibility criteria at the end of Visit 2 will be randomized to 
one of the three treatment groups utilizing the IWRS system. 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 
• AE Query 
• Subjects will be scheduled for Visit 3 
 
 
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8.3.4 Visit 3: Day 2 ± 2 hours, 24 h recovery post-CAE® 
•
Medical and Medication History Update
•
AE Query
•
Ora Calibra® Ocular Discomfort Scale
•
Ora Calibra® Ocular Discomfort & 4-Symptom 
Questionnaire
•
VAS Symptom Assessment
•
OSDI Questionnaire 
•
Visual Acuity (ETDRS)
•
Slit Lamp Biomicroscopy
•
Conjunctival Redness
•
TFBUT
•
Fluorescein Staining
•
Lissamine Green Staining
•
AE Query
•
Subjects will be scheduled for Visit 4
8.3.5 Visit 4: Day 4 ± 2 hours, 72 h recovery post-CAE® 
•
Medical and Medication History Update
•
AE Query
•
Ora Calibra® Ocular Discomfort Scale
•
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire
•
VAS Symptom Assessment
•
OSDI Questionnaire 
•
Visual Acuity (ETDRS)
•
Slit Lamp Biomicroscopy
•
Conjunctival Redness
•
TFBUT
•
Fluorescein Staining
•
Lissamine Green Staining
•
AE Query
•
Subjects will be scheduled for Visit 5
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8.3.6 Visit 5: Day 8 ± 1, 1-Week CAE® Follow-Up 
Pre–CAE® 
• Study Drug Kit and 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  
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• AE Query 
• 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 
• AE Query 
• Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site on 
Visit 5, 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 6. 
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8.3.7 Visit 6: Day 15 ± 1, 2-Week CAE® Follow-Up 
Pre–CAE® 
• Study Drug/Study Diary Collection 
• Confirm subject has NOT administered their morning study drug dose at home 
• 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  
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• AE Query 
• 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 6, 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 7 
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• Study Drug Instillation at the Study Site: Subjects will self-administer their study drug 
dose bilaterally at the study site under supervision of a trained technician 
• Ora Calibra® Drop Comfort Scale 
• AE Query 
• Subjects will be scheduled for Visit 7 
8.3.8 Visit 7: Day 29 ± 2, 4-Week CAE® Follow-Up 
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  
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
• AE Query 
• 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 
 
 
 
 
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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 
• AE Query 
• Study Exit  
 
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 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator 
 
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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 6 and given written instructions. To assess 
dosing and symptom assessment compliance, the subject daily diaries will be collected at Visit 2, 
5, 6, 7, and the subject’s used and unused study drug ampules will be collected at Visit 2, 5, 6, 
and 7. 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. 
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
•
lack of efficacy
•
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. 
COVID-19 Related Discontinuations will be indicated as well with a reason for COVID-19 
relatedness. 
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. 
STUDY TERMINATION 
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
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STUDY DURATION 
An individual subject’s participation will involve 7 visits over approximately a 35-days period (7 
days pre-screening, 28 days of treatment). 
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. 
 ADVERSE EVENTS 
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. 
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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: 
• 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. 
 
 
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9.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information about 
the IP using these explanations: 
• Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not listed 
at the specificity or severity that has been observed. 
• Expected: An AE that is listed in the Investigational Brochure (IB) at the specificity and 
severity that has been observed. 
• Not applicable: An AE unrelated to the IP. 
AEs 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. 
The investigator should initially classify the expectedness of an AE, but the final classification is 
subject to the Medical Monitor’s determination. 
 
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: 
• 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. 
• 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 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
 
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• A congenital anomaly/birth defect 
• 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 
 
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. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be immediately 
reported. All information relevant to the SAE must be recorded on the appropriate 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: 
 
Title: 
 
Office Telephone: 
 
Mobile Phone: 
 
Office Facsimile: 
 
 
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. 
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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. 
 PROTECTION OF HUMAN SUBJECTS 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject and/or from the 
subject’s parent or legal guardian prior to enrollment into the study.  
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. 
 ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
 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. 
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. 
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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. 
 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. 
 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. 
 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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REFERENCES 
Baratta, R.O., Schlumpf, E., Del Buono, B.J., DeLorey, S.S., Calkins, D.J. (2021). Corneal 
collagen as a potential therapeutic target in dry eye disease. Survey of Ophthalmology (in press). 
Hapach LA, VanderBurgh JA, Miller JP, Reinhart-King CA. Manipulation of in vitro collagen 
matrix architecture for scaffolds of improved physiological relevance. Phys Biol. 2015 Dec 
21;12(6):061002 
Kivanany PB, Grose KC, Yonet-Tanyeri N, Manohar S, Sunkara Y, Lam KH, Schmidtke DW, 
Varner VD, Petroll WM. An In Vitro Model for Assessing Corneal Keratocyte Spreading and 
Migration on Aligned Fibrillar Collagen. J Funct Biomater. 2018 Sep 21;9(4). 
CEQUA (2018). ""CEQUA (cyclosporine ophthalmic solution) 0.9% [drug label]." Sun 
Pharmaceuticals.". 
Fiscella, R. G. (2011). "Understanding dry eye disease: a managed care perspective." Am J 
Manag Care 17 Suppl 16: S432-439. 
Messmer, E. M. (2015). "The pathophysiology, diagnosis, and treatment of dry eye disease." 
Dtsch Arztebl Int 112(5): 71-81; quiz 82. 
Shetty, R., K. Deshpande, R. Deshmukh, C. Jayadev and R. Shroff (2016). "Bowman Break and 
Subbasal Nerve Plexus Changes in a Patient With Dry Eye Presenting With Chronic Ocular Pain 
and Vitamin D Deficiency." Cornea 35(5): 688-691. 
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APPENDICES 
 APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
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 APPENDIX 2: EXAMINATION PROCEDURES, TESTS, & EVALUATIONS  
Visual Acuity Procedures (ETDRS Chart) 
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Slit Lamp Biomicroscopy Procedures 
Undilated Fundoscopy 
 
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Intraocular Pressure (IOP) 
Unanesthetized Schirmer’s Test  
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Ocular Surface and Disease Index© (OSDI©) for Dry Eye 
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Visual Analog Scale (VAS) 
Tear Film Break-Up Time (TFBUT)  
Ora proprietary scales – Not for distribution without permission 
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Ora Calibra® Ocular Discomfort Scale for Dry Eye 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire for Dry Eye 
Fluorescein Staining  
 
 
 
 
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Ora Calibra® Corneal and Conjunctival Staining Scale for Grading of Fluorescein Staining 
 
 
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Page 57 of 68


Stuart Therapeutics  
Protocol 
Confidential
Page 58 of 68


Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 59 of 68


Stuart Therapeutics  
Protocol 
Confidential
Page 60 of 68


 
 
 
Stuart Therapeutics  
Protocol 
Confidential
Page 61 of 68


 APPENDIX 3: PROTOCOL AMENDMENT SUMMARY 
Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 62 of 68


Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 63 of 68


Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 64 of 68


Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 65 of 68


Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 66 of 68


 APPENDIX 4: SPONSOR AND ORA APPROVALS 
Protocol Title: 
A Phase 2 Multi-Center, Randomized, Double Masked, 
Placebo Controlled Study to Assess the Safety and 
Efficacy of ST-100 Ophthalmic Solution in Subjects 
Diagnosed with Dry Eye Disease 
IND Number 
143015 
Final Date:  
May 21, 2021 
This clinical study protocol was subject to critical review and has been approved by the sponsor. The 
Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 67 of 68


 APPENDIX 4: SPONSOR AND ORA APPROVALS 
Protocol Title: 
A Phase 2 Multi-Center, Randomized, Double Masked, 
Placebo Controlled Study to Assess the Safety and 
Efficacy of ST-100 Ophthalmic Solution in Subjects 
Diagnosed with Dry Eye Disease 
IND Number 
143015 
Final Date:  
May 21, 2021 
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. 
Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 67 of 68




APPENDIX 5: INVESTIGATOR’S SIGNATURE 
Protocol Title: 
IND Number 
Final Date:   
A Phase 2 Multi-Center, Randomized, Double Masked, 
Placebo Controlled Study to Assess the Safety and 
Efficacy of ST-100 Ophthalmic Solution in Subjects 
Diagnosed with Dry Eye Disease 
143015 
May 21, 2021 
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. 
Stuart Therapeutics  
ST-100 Ophthalmic Solution
Protocol 
IND 143015
Confidential
Page 68 of 68


Document History
SignNow E-Signature Audit Log
All dates expressed in MM/DD/YYYY (US)
Document name:
ST100-001 Protocol Amdendment 1 21May2021 Published-Unsigned
Document created:
05/24/2021 14:00:06
Document pages:
68
Document ID:
e382c109124e4354bd770979a1bd5858878c29dc
Document Sent:
05/24/2021 14:07:47 UTC
Document Status:
Pending
05/24/2021 14:08:06UTC

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase 2 Multi-Center, Randomized, Double Masked,
Placebo 
Controlled Study to Assess the Safety and Efficacy of ST-100
Ophthalmic Solution in Subjects Diagnosed with Dry Eye Disease
Sponsor:   
 
Stuart Therapeutics, Inc.
411 SE Osceola St., Suite 203 
Stuart, FL 34994 USA
 
 
 
 
Protocol Number:
ST100-001
Author:   
 
 
 
 
Date:    
 
25OCT2021
Version:  
 
1.0


Page 2 of 3 
A Phase 2 Multi-Center, Randomized, Double Masked, Placebo Controlled Study to 
Assess the Safety and Efficacy of ST-100 Ophthalmic Solution in Subjects 
Diagnosed with Dry Eye Disease
Protocol Number:
ST100-001
SAP Version:   
1.0
SAP Date:   
 
25OCT2021
Statistical Analysis Plan Approval


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Document History
SignNow E-Signature Audit Log
All dates expressed in MM/DD/YYYY (US)
Document name:
Stuart Therapeutics Inc ST100-001 SAP draft v1.0 25-OCT-2021 clean
Document created:
10/26/2021 14:28:35
Document pages:
48
Document ID:
2fce7f547f0b437bad5cd8831715c2c12a6b22a2
Document Sent:
10/26/2021 14:31:54 UTC
Document Status:
Signed
10/29/2021 17:36:43UTC


Protocol ST100-001 SAP, Version 1.0
25OCT2021
Confidential & Proprietary
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Table of Contents
1. 
Introduction ..............................................................................................................................8 
2. 
Study Objectives ......................................................................................................................8 
3. 
Study Variables........................................................................................................................8 
3.1 Primary Endpoints....................................................................................................................8 
3.2 Secondary Endpoints...............................................................................................................8 
3.3 Safety Variables .......................................................................................................................9 
3.4 Statistical Hypotheses..............................................................................................................9 
3.5 Estimands...............................................................................................................................10 
4. 
Study Design and Procedures ...............................................................................................11 
4.1 General Study Design............................................................................................................11 
4.2 Schedule of Visits and Assessments.....................................................................................11 
5. 
Study Treatments...................................................................................................................12 
5.1 Method of Assigning Subjects to Treatment Groups .............................................................12 
5.2 Masking and Unmasking........................................................................................................12 
6. 
Sample Size and Power Considerations................................................................................13 
7. 
Data Preparation....................................................................................................................13 
7.1 Input Data...............................................................................................................................13 
7.2 Output Data............................................................................................................................13 
8. 
Analysis Populations..............................................................................................................14 
8.1 Intent-to-Treat.........................................................................................................................14 
8.2 Per Protocol............................................................................................................................14 
8.3 Safety .....................................................................................................................................14 
9. 
General Statistical Considerations.........................................................................................14 
9.1 Unit of Analysis ......................................................................................................................14 
9.2 Missing or Inconclusive Data Handling..................................................................................14 
9.3 Definition of Baseline .............................................................................................................16 
9.4 Data Analysis Conventions ....................................................................................................16 
9.5 Adjustments for Multiplicity.....................................................................................................16 
10. 
Disposition of Subjects...........................................................................................................17 
11. 
Demographic and Pretreatment Variables.............................................................................18 
11.1 Demographic Variables..........................................................................................................18 
11.2 Baseline Disease Characteristics...........................................................................................18 
12. 
Medical History and Concomitant Medications......................................................................19 
12.1 Medical History.......................................................................................................................19 
12.2 Concomitant Medications.......................................................................................................19 


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12.3 Concomitant Procedures........................................................................................................20 
13. 
Dosing Compliance and Treatment Exposure .......................................................................20 
13.1 Dosing Compliance................................................................................................................20 
13.2 Treatment Exposure...............................................................................................................21 
14. 
Efficacy Analyses...................................................................................................................21 
14.1 Primary Analysis ....................................................................................................................21 
14.1.1 
Change from Baseline of Total Corneal Fluorescein Staining (Ora Calibra® Scale) in the 
Study Eye at Visit 7 (Day 29) Pre-CAE®.....................................................................................22 
14.1.1.1 
Primary Analysis Methods..................................................................................22 
14.1.1.2 
Multiple Imputation Methodology .......................................................................22 
14.1.1.3 
Additional Sensitivity Analyses...........................................................................25 
14.1.1.4 
Figures ...............................................................................................................26 
14.1.2 
Change from Baseline of Ocular Discomfort (Ora Calibra® Scale) in the Study Eye at Visit 7 
(Day 29) Pre-CAE® .....................................................................................................................26 
14.1.2.1 
Primary Analysis Methods..................................................................................26 
14.1.2.2 
Multiple Imputation Methodology .......................................................................26 
14.1.2.3 
Additional Sensitivity Analyses...........................................................................28 
14.1.2.4 
Figures ...............................................................................................................28 
14.2 Secondary Analyses ..............................................................................................................28 
14.2.1 
Analysis of Secondary Endpoints...............................................................................29 
14.2.2 
Corneal and Conjunctival Fluorescein staining (Ora Calibra® scale).........................30 
14.2.3 
Corneal and Conjunctival Lissamine Green staining (Ora Calibra® scale)................30 
14.2.4 
Tear Film Break-Up Time...........................................................................................30 
14.2.5 
Conjunctival Redness (Ora Calibra Scale) ................................................................31 
14.2.6 
Drop Comfort Assessment.........................................................................................31 
14.2.7 
Ocular Surface Disease Index ...................................................................................31 
14.2.8 
Overall Ocular Discomfort & 4-Symptom Questionnaire (Ora Calibra® Scale)..........32 
14.2.9 
Ocular Discomfort Scale (Ora Calibra® Scale)...........................................................32 
14.2.9.1 
Ocular Discomfort Outside of the CAE®.............................................................33 
14.2.9.2 
Ocular Discomfort During the CAE®...................................................................33 
14.2.10 
Visual Analog Scale ...................................................................................................33 
14.2.11 
Unanesthetized Schirmer’s Test ................................................................................33 
15. 
Summary of Efficacy Analyses ..............................................................................................34 
16. 
Safety Analyses .....................................................................................................................34 
16.1 Adverse Events ......................................................................................................................34 
16.2 Best-Corrected Visual Acuity (Early Treatment Diabetic Retinopathy Study) .......................36 
16.3 Slit-Lamp Biomicroscopy Examination...................................................................................36 
16.4 Intraocular Pressure ...............................................................................................................37 
16.5 Undilated Fundoscopy Examination ......................................................................................37 
16.6 Urine Pregnancy Test ............................................................................................................37 


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17. 
Interim Analyses.....................................................................................................................37 
18. 
Changes from Protocol-Stated Analyses...............................................................................37 
19. 
References.............................................................................................................................37 
20. 
Revision History .....................................................................................................................37 
21. 
Tables.....................................................................................................................................38 
22. 
Listings ...................................................................................................................................41 
23. 
Figures ...................................................................................................................................43 
24. 
Appendices ............................................................................................................................44 
24.1 Appendix 1: Schedule of Visits and Measurements ..............................................................44 


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List of Abbreviations
ADaM
Analysis Data Model
AE
Adverse Event
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical
BCVA
Best-Corrected Visual Acuity
BID
Bis in die (Twice Daily)
CAE®
Controlled Adverse Environment
CFB
Change from Baseline
CFV2-Post
Change from Visit 2 (Day 1) Post-CAE®
CI
Confidence Interval
CRO
Contract Research Organization
CS
Clinically Significant
DED
Dry Eye Disease
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ETDRS
Early Treatment of Diabetic Retinopathy Study
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IOP
Intraocular Pressure
IP
Investigational Product
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LOCF
Last Observation Carried Forward
logMAR
Logarithm of the Minimum Angle of Resolution
LS
Least Squares
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
NCS
Not Clinically Significant
OD
Oculus dexter (Right Eye)
OS
Oculus sinister (Left Eye)
PDF
Portable Document Format
PMM
Pattern Mixture Model
PP
Per Protocol
PT
Preferred Term
RTF
Rich Text Format
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDC
Statistics & Data Corporation
SDTM
Study Data Tabulation Model
SE
Standard Error


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SOC
System Organ Class
TEAE
Treatment-Emergent Adverse Event
TFBUT
Tear Film Break-Up Time
TMF
Trial Master File
WHODrug
World Health Organization Drug Dictionary


Protocol ST100-001 SAP, Version 1.0
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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol amendment 1 dated 21-MAY-2021.
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, the most recent ICH E9 (R1) Guideline entitled Guidance for Industry: 
Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials, and 
the most recent ICH E3 Guideline entitled Guidance for Industry: Structure and Content of Clinical Study 
Reports.
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. Study Objectives
The objective of this study is to compare the safety and efficacy of two different concentrations of ST-100 
Ophthalmic Solution to placebo for the treatment of the signs and symptoms of dry eye.
3.
Study Variables
3.1
Primary Endpoints 
The primary efficacy endpoints are the following: 
x
Sign: Total corneal fluorescein staining score on the Ora Calibra® scale, measured by 
 
 
x
Symptom: Ocular discomfort score on the Ora Calibra® Ocular Discomfort Scale, measured by 
 
3.2 
Secondary Endpoints 
The secondary efficacy endpoints include the following:
x
Fluorescein staining (Ora Calibra® scale) at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and Pre- 
to Post-CAE®): regions: 
 
 
x
Lissamine green staining (Ora Calibra® scale) at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, 
and Pre- to Post-CAE®): regions:
 


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x
Tear film break-up time (TFBUT) at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and Pre- to Post-
CAE®) 
x
Conjunctival Redness at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and Pre- to Post-CAE®) 
x
Drop comfort assessment after randomization at Visit 2 and Visit 6
x
Ocular Surface Disease Index (OSDI©) at Visits 3, 4, 5, 6, and 7 (Pre-CAE®) 
x
Overall Ocular Discomfort and Four-symptom Questionnaire at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, 
Post-CAE®, and Pre- to Post-CAE®) 
x
Ocular discomfort during CAE® at Visits 5, 6, and 7
x
Daily diary
x
Visual Analog Scale – Burning/Stinging, Itching, Foreign Body Sensation, Blurred Vision, Eye 
Dryness, Photophobia, and Pain at Visits 3, 4, 5, 6, and 7 (Pre-CAE®) 
x
Unanesthetized Schirmer’s Test at Visit 7 (Pre-CAE®) 
x
Ocular Discomfort Scale outside of the CAE® at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and 
Pre- to Post-CAE®) 
3.3
Safety Variables
The safety variables include the following:
x
Best-corrected visual acuity (BCVA)
x
Slit-lamp evaluation
x
Adverse event (AE) query
x
Intraocular pressure (IOP)
x
Undilated fundoscopy
3.4
Statistical Hypotheses
The primary endpoints will be tested for 
The statistical hypotheses are stated in terms of 
 
 
 
 
 


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3.5
Estimands
The primary comparisons in this trial will be between ST-100 Ophthalmic Solution (high dose or low dose) 
versus placebo at Day 29 in the Intent-to-Treat (ITT) population with multiple imputation using the following 
primary estimand:
Estimand 1:
x
Population: 
x
Endpoint:
 
x
Intercurrent event:
 
 
  
 
  


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x
Population-level summary:
 
 
  
 
4.
Study Design and Procedures
4.1
General Study Design
Study visits will be referred to in all tables and listings as the visit number and expected study day 
corresponding to the visit to enable reviewers to understand the assessment timing without referring to the 
protocol visit schedule. Table 1 shows the scheduled study visits, their planned study day (note: that there 
is no Day 0 and that Day 1 corresponds to the day of randomization), and the acceptable visit window for 
each study visit:
Table 1. Study Visit Windows 
Scheduled Visit
Planned Study Day
Visit Window
Visit 1
Day -7
± 1 day
Visit 2
Day 1
N/A
Visit 3
Day 2
± 2 hours
Visit 4
Day 4
± 2 hours
Visit 5
Day 8
± 1 day
Visit 6
Day 15
± 1 day
Visit 7
Day 29
± 2 days
4.2
Schedule of Visits and Assessments
The schedule of visits and assessments is provided in Appendix 1. 


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5.
Study Treatments
5.1
Method of Assigning Subjects to Treatment Groups
Before the initiation of study run-in at Visit 1 (Day -7), 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 skipped or omitted. Each subject who meets all the inclusion and none of the 
exclusion criteria at Visit 1 (Day -7) and Visit 2 (Day 1) will be assigned a randomization number at the end 
of Visit 2 (Day 1). The Interactive Web Response System (IWRS) will be used to assign all randomization 
numbers.
Subjects will be randomized to one of the following treatment arms at Visit 2 (Day 1):
x
Low dose ST-100 Ophthalmic Solution: 
x
High dose ST-100 Ophthalmic Solution: 
x
Placebo Ophthalmic Solution (Vehicle): 
Approximately 
 subjects will be randomly assigned to one of the three groups (1:1:1) to receive either 
ST-100 Ophthalmic Solution or placebo solution as topical ophthalmic drops administered bilaterally BID 
for 4 weeks. Subjects, Sponsor, Contract Research Organization (CRO), and site personnel will be masked 
to treatment assignment. Randomization and kit numbers will be assigned automatically to each subject as 
they are entered into the 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.
5.2
Masking and Unmasking
All subjects, investigators, and study personnel involved with the conduct of the study will be masked with 
regard to treatment assignments. When medically necessary, the investigator may need to determine what 
treatment 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 investigational product 
(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 


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Page 13 of 14
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 AE or study completion, whichever occurs last.
6.
Sample Size and Power Considerations
This study is expected to enroll 
 subjects in each group, for a total of 
 randomized subjects. 
Approximately 
 subjects will be screened. Assuming a 10% drop out rate, 
 subjects per group are 
expected to complete the study.  
7.
Data Preparation
7.1
Input Data
Study data will primarily be recorded on the eCRFs supplied by Statistics & Data Corporation (SDC) using 
iMedNet v1.211.1.
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:
x 
Database lock has occurred with written authorization provided by appropriate SDC and Sponsor 
personnel. 
x
Protocol deviations have been identified and status defined (major/minor deviations) prior to 
database lock. 
x
Analysis populations have been determined. 
x
Randomized treatment codes have been unmasked. 
7.2
Output Data
Data from electronic data capture (EDC) and external data will be transferred to Biostatistics and 
incorporated into standard formats following the Study Data Tabulation Model (SDTM). Data will then be 
mapped to analysis datasets using the Analysis Data Model (ADaM).  Both SDTM- and ADaM-formatted 
data will be used to create the subject listings, while all tables and figures will be based on the ADaM-
formatted data.
SDTM will follow the SDTM version 1.7 model and will be implemented using the SDTM Implementation 
Guide version 3.3, and the most recent version of SDTM Controlled Terminology at the start of the study. 
ADaM data will follow the ADaM version 2.1 model and will be implemented using the ADaM 


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Page 14 of 15
Implementation Guide version 1.2. Both SDTM and ADaM will be validated using Pinnacle 21 version 3.1.2. 
Any discrepancies in the validation will be noted in reviewer’s guides accompanying the final data transfers.
Define.xml will be created for SDTM and ADaM using the Define-XML version 2.0 model.
8.
Analysis Populations
8.1 
Intent-to-Treat
The intent-to-treat (ITT) population includes
 
 
 
8.2
Per Protocol
The per protocol (PP) population includes 
 
 
 
 
8.3
Safety
The safety population includes 
 
 
 
9.
General Statistical Considerations
9.1
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 (Worst) Eye: 
 
 
 
9.2
Missing or Inconclusive Data Handling 
Imputation of missing data will be executed for partial or missing dates where complete dates are required 
to flag data as treatment-emergent or concomitant with treatment. Partial/missing start and end dates for 
AEs and concomitant medications will be imputed as follows:
Partial/missing start date: 


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Page 15 of 16
x
Dates with missing day only will be imputed as the 1st of the month unless the month and year are
same as the month and year of first dose of study medication, in which case missing day will be 
imputed as the first dose day of study medication. 
x
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as the 
first dose day and month of study medication. 
x
Completely missing dates will be imputed as the first dose date of study medication unless the end 
date is on or before the first dose date of study medication, in which case missing date will be 
imputed as 1 Jan of the same year as the end date.
Partial/missing end date: 
x
Dates with missing day only will be imputed as the last day of the month unless the month and year
are the same as the month and year of the last dose of study medication, in which case missing 
day will be imputed as the last dose day of study medication. 
x
Dates with both day and month missing will be imputed as 31 Dec unless the year is same as the 
year of the last dose of study medication, in which case missing day and month will be imputed as 
the last dose day and month of study medication.  
x
If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is 
available, in which case the missing date will be imputed as the death date. If ongoing is “No” then
the missing end date will be imputed as the last dose date.
x
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death.
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc).
Missing data for the primary efficacy endpoints will be imputed using multiple imputation on the ITT 
population as specified in Estimand 1 for primary analyses.
Sensitivity analyses of the primary efficacy analyses will include the following in order to provide a robust 
understanding of the impact of missing and spurious data:
 
  


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9.3
Definition of Baseline
Baseline measures are defined as 
 
 
 
 
 
 
9.4
Data Analysis Conventions
All data analysis will be performed by SDC after the study is completed and the database has been locked 
and released for unmasking. 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. All study data will be listed by subject, 
treatment, and visit (as applicable) based on all randomized subjects unless otherwise specified.
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 groups and placebo will be calculated as active minus placebo and change from baseline 
will be calculated as follow-up visit minus baseline.  
 
 
 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit.
Listings will be sorted by treatment group, subject number, visit/time point, and parameter as applicable. 
9.5
Adjustments for Multiplicity
 
 
 


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10. Disposition of Subjects
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
included in the following analysis populations: 
 
Subjects who are not discontinued from the study will be considered study 
completers. Disposition will be summarized by 
 
  
The total number of screened subjects with the number and percentage of screen failure subjects. 
The reasons for premature study discontinuation will be summarized by treatment group for all discontinued
subjects. Percentages will be calculated using discontinued subjects as the denominator. The reasons for 
study discontinuation that will be summarized include: AE, protocol violation, administrative reasons, 
sponsor termination of study, subject choice, lost to follow-up, lack of efficacy, and other. The subset of 
COVID-19-related discontinuations will be summarized as well. A subject listing will be provided that 
includes the date of and reason for premature study discontinuation. The listing will indicate COVID-19
relatedness with a reason for COVID-19 relatedness.
 
 
 


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For all screen failures, the reasons for screen failure will be displayed with the percentages calculated using 
total number of screen failures as the denominator.  
In addition, subject listings will be provided that include informed consent date, screen failure reason, and 
exclusions from analysis populations. Details of the study randomization, including randomization date and 
time, randomized treatment, and actual treatment, will also be included within a subject listing. A listing 
summarizing all COVID-19-related discontinuations and protocol deviations will be generated as well.
11. Demographic and Pretreatment Variables
11.1 
Demographic Variables
The demographic variables collected in this study include age, sex, childbearing potential for female 
subjects, race, ethnicity, and iris color. Subjects who record more than one race will be grouped into a 
single category denoted as Multiple. Iris color will be summarized at the eye level (OD and OS). 
Demographic variables will be summarized for the ITT and Safety populations, separately.
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics. Age will 
DOVREHFDWHJRUL]HGDVIROORZV
$JHZLOOEHUHSRUWHGin years and calculated using 
the following formula:
The number and percentage of subjects will be presented, overall and by treatment, for age category, sex, 
race, ethnicity, and iris color.  
A subject listing that includes all demographic variables will be provided for all screened subjects. 
11.2
Baseline Disease Characteristics  
Baseline disease characteristics will be summarized by treatment group using 
 
 
 
 
 


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12. Medical History and Concomitant Medications
12.1
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 24.0. 
Ocular and non-ocular medical history will be summarized separately
 
 
 
 
 
Listings of medical history will be generated separately for ocular and non-ocular data.
12.2 
Concomitant Medications
Concomitant medications will be coded using World Health Organization Drug Dictionary (WHODrug)
Global (B3, March 2021) 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 lowest 
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. Any uncoded terms will be 
summarized under the ATC classification and preferred name of “Uncoded.”
Concomitant medications are defined as those medications listed as having been taken (1) prior to initiation 
of randomized study drug administration and continuing for any period of time following the first 
administration of randomized study drug or (2) at any time following the first administration of randomized 
study drug. Prior medications are defined as those listed as having been prior to initiation of randomized 
study drug administration but not taken for any instance following the first administration of randomized 
study drug.
 
 
 
 
 


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Listings of concomitant medications will be generated separately for ocular and non-ocular data.
12.3
Concomitant Procedures
Concomitant procedures will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
24.0.
 
 
 
 
 
Listings of concomitant procedures will be generated separately for ocular and non-ocular data.
13. Dosing Compliance and Treatment Exposure
13.1
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:
The number of actual doses received will be calculated from the number of used ampules from the study 
drug accountability eCRF. The number of expected doses that will be used for calculating compliance will 
be calculated as:  
 
for all subjects with exception of subjects that are lost to follow-up. The number of expected doses for 
subjects that are lost to follow-up will be calculated as:
 
The number of expected doses for subjects who discontinue on visit 2 will be 2 doses. 
A categorical dosing compliance variable will also be derived as non-compliant 
FRPSOLDQW
 and over compliant
Dosing compliance (%) will be summarized with continuous descriptive statistics for each treatment group
using the Safety population. The compliance category defined above will be summarized with discrete 
summary statistics.  


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A subject listing of dosing compliance will also be produced. In addition, the following listings will be 
produced for all randomized subjects:
x
run-in and study drug assignment, dispensation, replacement, and study drug instillation; 
x
study drug accountability;
13.2
Treatment Exposure
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following:
  
Extent of treatment exposure for subjects who were lost to follow-up will be calculated in days using the 
following:
 
The extent of treatment exposure for subjects who discontinue on Visit 2 (Day 1) will be 1 day. 
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. Total exposure in days will be 
summarized for each treatment group as well. A subject listing of treatment exposure will also be produced.
14. Efficacy Analyses
14.1
Primary Analysis
The primary efficacy endpoints are the following:
 
 
 
 
 
 
 
 
 
 


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14.1.1 CHANGE FROM BASELINE OF TOTAL CORNEAL FLUORESCEIN STAINING (ORA CALIBRA® SCALE) IN THE 
STUDY EYE AT VISIT 7 (DAY 29) PRE-CAE®
 
 
 
14.1.1.1 
PRIMARY ANALYSIS METHODS
 
 
 
 
 
 
 
 
 
 
 
 
14.1.1.2 
MULTIPLE IMPUTATION METHODOLOGY
 
 
 
 
 
 
 
  
 
  
 


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14.1.1.4 
FIGURES
 
 
14.1.2 CHANGE FROM BASELINE OF OCULAR DISCOMFORT (ORA CALIBRA® SCALE) IN THE STUDY EYE AT VISIT 
7 (DAY 29) PRE-CAE® 
 
 
 
14.1.2.1 
PRIMARY ANALYSIS METHODS
 
 
 
 
 
 
 
 
 
 
14.1.2.2 
MULTIPLE IMPUTATION METHODOLOGY
 
 
 
  
 
  
 
  
 


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14.1.2.3 
ADDITIONAL SENSITIVITY ANALYSES
Additional sensitivity analyses will be conducted as described in Section 14.1.1.3. 
14.1.2.4 
FIGURES
 
 
 
14.2
Secondary Analyses
The secondary efficacy variables include the following:
x
Fluorescein staining (Ora Calibra® scale) at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and 
Change from Pre-CAE® to Post-CAE®): regions: 
 
 
x
Lissamine green staining (Ora Calibra® scale) at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, 
and Pre- to Post-CAE®): regions: 
 
 
x 
TFBUT at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and Change from Pre-CAE® to Post-
CAE®) 
x
Conjunctival Redness at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and Change from Pre-
CAE® to Post-CAE®) 
x
Drop comfort assessment after randomization at Visit 2 and Visit 6
x
OSDI© at Visits 3, 4, 5, 6, and 7 (Pre-CAE®) 
x
Four symptom questionnaire at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and Change from 
Pre-CAE® to Post-CAE®) 
x
Ocular discomfort during CAE® at Visits 5, 6, and 7
x
Daily diary
x
Visual Analog Scale – Burning/Stinging, Itching, Foreign Body Sensation, Blurred Vision, Eye 
Dryness, Photophobia, and Pain at Visits 3, 4, 5, 6, and 7 (Pre-CAE®) 


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x
Unanesthetized Schirmer’s Test at Visit 7 (Pre-CAE®) 
x
Ocular Discomfort Scale outside of the CAE® at Visits 3, 4, 5, 6, and 7 (Pre-CAE®, Post-CAE®, and 
Change from Pre-CAE® to Post-CAE®) 
14.2.1 ANALYSIS OF SECONDARY ENDPOINTS
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Subject listings will be provided for all efficacy endpoint assessments for randomized subjects only. 


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14.2.2 CORNEAL AND CONJUNCTIVAL FLUORESCEIN STAINING (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
 
 
 
14.2.3 CORNEAL AND CONJUNCTIVAL LISSAMINE GREEN STAINING (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
 
 
14.2.4 TEAR FILM BREAK-UP TIME
 
 


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14.2.5 CONJUNCTIVAL REDNESS (ORA CALIBRA SCALE) 
 
 
 
 
 
14.2.6 DROP COMFORT ASSESSMENT 
 
 
 
 
 
 
14.2.7 OCULAR SURFACE DISEASE INDEX


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14.2.8 OVERALL OCULAR DISCOMFORT & 4-SYMPTOM QUESTIONNAIRE (ORA CALIBRA® SCALE) 
 
 
 
 
 
 
 
14.2.9 OCULAR DISCOMFORT SCALE (ORA CALIBRA® SCALE) 
 
 


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. 
14.2.9.1 
OCULAR DISCOMFORT OUTSIDE OF THE CAE®
Analyses will be conducted as described in Section 14.2.1. 
 
 
14.2.9.2 
OCULAR DISCOMFORT DURING THE CAE®
 
 
 
 
 
14.2.10 VISUAL ANALOG SCALE
 
 
 
 
 
 
 
14.2.11 UNANESTHETIZED SCHIRMER’S TEST
 
 
 
 
 
Analyses will be conducted as described in Section 14.2.1. 


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15. Summary of Efficacy Analyses
 
 
 
 
16. Safety Analyses
All safety analyses will be conducted using the safety population.
16.1
Adverse Events
An AE is defined as any untoward medical occurrence associated with the use of an IP in humans, whether 
or not considered IP-related. An AE can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IP, without any judgment 
about causality. An AE can arise from any use of the IP (e.g., off-label use, use in combination with another 
drug or medical device) and from any route of administration, formulation, or dose, including an overdose. 
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 will be coded using the MedDRA 24.0.
Treatment-emergent adverse events (TEAE) are defined as any event that occurs or worsens on or after 
the first dose of randomized study drug..
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 study drug or seriousness of the event and should be evaluated according to the following 
scale:
x
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities.
x
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with the 
subject’s daily activities.
x
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and interferes 
with the subject’s daily activities.
The relationship of each AE to the IP should be determined by the investigator using these explanations:


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x
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.
x
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.
x
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.
x
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.
x
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. 
TEAEs that are recorded as definitely related, probably related, and possibly related are considered as 
treatment-related TEAEs. 
The expectedness of an AE should be determined based upon existing safety information about the IP 
using these explanations:
x
Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not listed at the 
specificity or severity that has been observed.
x
Expected: An AE that is listed in the IB at the specificity and severity that has been observed.
x
Not applicable: An AE unrelated to the IP.
All AEs 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
An overall summary will be presented that includes the number of events and the number and percentage 
of subjects who experienced at least one AE, ocular AE, and non-ocular AE by treatment group and over 
all subjects. This summary will also include the number of events and the number and percentage of 
subjects who experienced at least one TEAE, as well as breakdowns of TEAEs further categorized as 
ocular or non-ocular, TEAEs by severity, TEAEs by relationship to study drug, TEAEs causing premature 
treatment discontinuation, and SAEs. TE-SAEs will also be categorized as ocular or non-ocular, TE-SAEs 
by severity, TE-SAEs by relationship to study drug, TE-SAEs causing premature treatment discontinuation, 
and TE-SAEs leading to death. 
Summaries will be provided for the following categories of AEs: 


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x
Ocular and non-ocular TEAEs by SOC and PT
x
Ocular and non-ocular TEAEs by SOC, PT, and maximal severity
x
Ocular and non-ocular treatment-related TEAEs by SOC and PT
x
Ocular and non-ocular TE-SAEs by SOC and PT 
x
Ocular and non-ocular TEAEs by SOC, PT and study day of onset (Day 8 or prior, After Day 8 to 
Day 15, and After Day 15 to Day 29). 
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 and PTs within SOCs will be listed in order of descending 
frequency for all subjects.  
All AEs for screened subjects, ocular AEs, non-ocular AEs, and SAEs for randomized subjects will be 
presented in subject listings. 
16.2
Best-Corrected Visual Acuity (Early Treatment Diabetic Retinopathy Study) 
 
 
 
 
 
16.3
Slit-Lamp Biomicroscopy Examination
 
 
 
 
 
 


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16.4
Intraocular Pressure
 
 
 
 
16.5
Undilated Fundoscopy Examination
 
 
 
 
 
 
 
16.6
Urine Pregnancy Test
 
 
17. Interim Analyses
No interim analyses are planned.
18. Changes from Protocol-Stated Analyses
CFB-V2 Post as defined in section 9.3 of this SAP will be analyzed at Visit 3 (Day 2), Visit 4 (Day 4),Visit 5 
(Day 8) Pre-CAE®, Visit 6 (Day 15) Pre-CAE®, and Visit 7 (Day 29) Pre-CAE®. 
19. References
There are no applicable references for this SAP.
20. Revision History
Documentation of revision to the SAP will commence after approval of the final version 1.0. 


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21. Tables 
Tables (10 tables total) that will be included in the topline delivery are shown in boldface font.  


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23. Figures 


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24. Appendices 
24.1
Appendix 1: Schedule of Visits and Measurements


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