Clinical trial NCT05723770
Conditions: Dry Eye Disease (DED)
Sponsor: Bausch & Lomb Incorporated
Start date: 2023-08-14; Completion date: 2023-12-23
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Determine the effect of a single instillation of NOV03 on the thickness and evaporation rate of the mucus-aqueous layer of the tear film

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: instillation of NOV03
Intervention descriptions: intervention 1: This trial consists of 2 office visits over a period of approximately 2 weeks. At Visit 2, a designated clinical staff member or the investigator will instill 1 drop of NOV03 into each eye.

Protocol documents:
Prot_SAP_002.pdf: 
NOV03 (Perfluorohexyloctane) 
Clinical Trial Protocol #922 
Sponsor: Bausch & Lomb Incorporated 
Oct 16th 2023 FINAL v3.0 
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TITLE PAGE 
Clinical Trial Protocol: 922 
 
 
Protocol Title: 
Effects of NOV03 on the Tear Film in Subjects with Dry Eye 
Disease 
Protocol Number: 
922 
Study Phase: 
4 
Investigational Product Name: 
Perfluorohexyloctane (NOV03; MIEBO™) 
IND Number: 
130558 
Indication: 
Signs and symptoms of dry eye disease 
Investigator: 
 
 
 
 
Sponsor: 
Bausch & Lomb Incorporated 
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
Contract Research Organization: 
NA 
IRB/IEC: 
Miami VA Institutional Review Board 
 
 
 
 
Date 
Original Protocol: 
23rd Jan 2023 
Amendment 2: 
16th Oct 2023 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Bausch & Lomb Incorporated. Further 
dissemination, distribution or copying of this protocol or its contents is strictly prohibited. 




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INVESTIGATOR’S SIGNATURE 
 
 
 
 
Protocol Title: 
Effects of NOV03 on the Tear Film in Subjects with Dry Eye Disease 
Protocol Number: 
922 
Final Date: 
16th Oct 2023 
 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, good 
clinical practices and all applicable laws and regulations. I agree to maintain all information supplied by 
Ora and the sponsor in confidence and, when this information is submitted to an Institutional Review 
Board (IRB), Ethical Review Committee (ERC) or another group, it will be submitted with a designation 
that the material is confidential. 
 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects. 
 
 
 
 
 
 
 
 
 
 
 


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SPONSOR PERSONNEL 
 
 
 
Sponsor: 
Bausch & Lomb Incorporated 
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
Sponsor Representative: 
 
 
 
 
 
 
 
 
 
MEDICAL MONITOR 
 
Medical Monitor: 
 
 
 
 
 
 
 


NOV03 (Perfluorohexyloctane) 
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SYNOPSIS 
 
Protocol Title: 
Effects of NOV03 on the Tear Film in Subjects with Dry Eye 
Disease 
Protocol Number: 
922 
Investigational Product: 
Perfluorohexyloctane (PFHO; MIEBO™; NOV03) 
Study Phase: 
4 
Primary Objective(s): 
Determine the effect of a single instillation of PFHO on the 
thickness and evaporation rate of the mucus-aqueous layer of 
the tear film 
Exploratory Objective(s): 
 
 
Overall Study Design: 
Structure: 
This pilot, open label, single-arm, single-center study will 
consist of 2 study visits in subjects with dry eye disease 
associated with MGD. A Screening Visit will occur to verify 
subjects are eligible to participate followed by an Assessment 
Visit to evaluate tear film parameters at baseline and over 
approx. 4 hours following a single instillation of PFHO. 
Screening Visit: At Visit 1, the subjects will complete the 
informed consent process followed by a screening visit to 
determine the presence of dry eye and associated MGD, which 
will include slit-lamp exam, visual acuity (VA), intraocular 
pressure (IOP), meibomian gland dysfunction (MGD) 
assessment, Schirmer test, tear film break up time (TFBUT), 
corneal fluorescein staining (CFS), and ocular surface disease 
index (OSDI). 
Assessment Visit: At Visit 2, a slit lamp examination and two 
baseline tear film assessments will be performed (tear film 
parameters: mucus-aqueous layer thickness (MALT); mucus- 
aqueous thinning rate (MALTR); 
 
 
 Then 1 
drop of PFHO will be instilled into both eyes (the study eye 
will be the eye with the highest corneal fluorescein staining). 
The above assessments will be repeated at multiple time 
points up to 4 hours post-instillation (time points: 5±1 min, 
15±2 min, 30±2 min, 60±5 min, 120±10 min, 240±10 min). 
Any adverse events will be recorded. 


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Duration: 
This trial consists of 2 office visits over a period of 
approximately 2 weeks. 
Controls: 
None (single-arm study) 
Dosage Instillation: 
At Visit 2, a designated clinical staff member or the 
investigator will instill 1 drop of PFHO into each eye. 
Summary of Visit Schedule: 
Visit 1 (Day -14 to Day 0): Screening / Informed Consent 
Visit 2 (Day 1): Tear film parameters before and after PFHO 
instillation 
Measures Taken to Reduce Bias: 
NA 
Study Population Characteristics: 
Number of Subjects: 
Approximately 50 subjects will be screened in order to enroll 
approximately 30 subjects 
Condition/Disease: 
Dry eye disease associated with meibomian gland dysfunction 
Inclusion Criteria: 
General/Ocular Inclusion Criteria 
1. Will be at least 18 years of age at the time of consent. 
2. Able to provide written voluntary informed consent. 
3. Have a subject-reported history of DED in both eyes 
for at least 6 months prior to Visit 1. 
4. Have Tear film break-up time (TFBUT) <10 sec at 
Visit 1. 
5. Have Meibomian Gland Dysfunction (MGD) defined 
as total MGD score ≥ 3 (secretion of 5 central glands 
on lower eyelid will be evaluated, each will be scored 
from 0-3; 0 = normal, 1 = thick/yellow, whitish, 
particulate 2 = paste; 3 = none/occluded; total score will 
range from 0-15) at Visit 1. 
6. Have a total corneal fluorescein staining score of ≥2 
and ≤11 (i.e. sum of inferior, superior, central, nasal, 
and temporal) according to the National Eye Institute 
(NEI) scale at Visit 1. 
7. Have at least one eye that satisfies all criteria for 4-6 
above at Visit 1. 
8. Is able to fix his/her gaze for a minute, i.e. can see the 
fixation target and with no nystagmus 
9. Is able and willing to follow instructions, including 
participation in all trial assessments and visits. 
Exclusion Criteria: 
General/Ocular Exclusion Criteria 
1. Have any clinically significant ocular surface slit-lamp 
findings at Visit 1 and Visit 2 and/or in the opinion of 


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the Investigator had any findings that may have 
interfered with trial parameters, including 
a. history of eye trauma 
b. history of Stevens-Johnson syndrome 
c. active blepharitis or lid margin inflammation 
d. DED secondary to scarring, irradiation, alkali 
burns, cicatricial pemphigoid, or destruction of 
conjunctival goblet cells (as with vitamin A 
deficiency). 
e. abnormal lid anatomy that caused incomplete 
eyelid closure 
f. abnormal cornea shape (keratoconus) 
g. corneal epithelial defect or significant 
confluent staining or filaments 
h. history of herpetic keratitis. 
i. has a pterygium in either eye. 
j. ocular or periocular rosacea that in the 
judgement of the Investigator interfered with 
the trial 
2. Has used any topical ocular steroids treatments, 
prescription dry eye therapy including varenicline 
nasal spray, or topical anti-glaucoma medication 
within 60 days prior to Visit 1. 
3. Have had a LipiFlow procedure within 1 month prior 
to Visit 2. 
4. Have received a permanent punctum plug within 3 
months (6 months for dissolvable punctum plugs) 
prior to Visit 2. Have removed a permanent punctum 
plug within 1 month prior to Visit 2. 
5. Have used any eye drops (prescription or artificial 
tears) and/or TrueTearTM device (intranasal tear 
neurostimulator) within 24 hours before Visit 2. 
6. Have active ocular allergies or ocular allergies that are 
expected to be active during the trial period. 
7. Have worn contact lenses within 1 month of Visit 1 or 
anticipate using contact lenses during the trial. 
8. Have undergone intraocular surgery or ocular laser 
surgery within the previous 6 months or had any 
planned ocular and/or lid surgeries over the trial 
period. 
9. Have an active ocular or systemic infection (bacterial, 
viral, or fungal), including fever requiring treatment 
with antibiotics. 
10. Is a woman who was pregnant, nursing or planning a 
pregnancy. 
11. Is a woman of childbearing potential who is not using 
an acceptable means of birth control; acceptable 
methods of contraception included: hormonal (oral, 


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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 
could have been regarded as an adequate method of 
birth control; however, if the subject becomes sexually 
active during the trial, she must agree to use adequate 
birth control as defined above for the remainder of the 
trial. 
12. Has an uncontrolled systemic disease in the opinion of 
the Investigator will interfere with the trial. 
13. Has a known allergy and/or sensitivity to the 
investigational drug. 
14. Has used any oral medications known to cause ocular 
drying (e.g., antihistamines, antidepressants, etc.) on a 
non-stable regimen within 1 month prior to Visit 1 or 
is expected to be unstable during the trial. 
15. Have taken isotretinoin (e.g. Accutane, Myorisan, 
Claravis, Amnesteem) within 6 months of Visit 1. 
16. Has corrected VA worse than or equal to logarithm of 
the minimum angle of resolution (LogMAR), +0.7 as 
assessed with Early Treatment Diabetic Retinopathy 
Study (ETDRS) charts in both eyes at Visit 1. 
17. Is currently enrolled in an investigational drug or 
device study or had used an investigational drug or 
device within 60 days of Visit 2. 
Study Formulations: 
Test Article: Perfluorohexyloctane 
Efficacy Measures and Endpoints: 
Primary Efficacy Measures 
• Mucus-aqueous layer thickness (MALT) and thinning rate 
(MALTR) at baseline and at multiple time points following 
instillation of PFHO 
 
 
 
 
 
 
Safety Measures: 
• 
Adverse Events (AEs; reported, elicited and observed) 
General Statistics 
Continuous variables will be summarized using the mean, standard deviation, median, minimum, and 
maximum. Categorical variables will be summarized using frequencies and percentages. 
Analysis Populations 


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Full Analysis Set (FAS): The FAS will consist of all enrolled subjects who are instilled with study drug 
Per Protocol Set (PP Set): The PP Set will consist of FAS subjects with no protocol violations expected 
to affect the evaluability of efficacy. 
Safety Analysis 
The number and percentage of subjects with specific treatment-emergent adverse events (TEAEs) will 
be summarized for each treatment group. The number of subjects will be tabulated by MedDRA System 
Organ Class and preferred term within each system organ class. 
Primary Efficacy Analyses 
The primary comparison in this trial is CFB in MALTR and MALT following a single instillation of 
PFHO. Change from baseline (post-instillation minus baseline, average of 2 baseline readings) at each 
post instillation time point will be summarized using continuous summary statistics. 
Hypotheses 
For each primary endpoint at each post-instillation timepoint, the null hypothesis is that the mean 
change from baseline is zero. The alternative hypothesis is that the mean change from baseline is not 
zero. 
Methods 
Each primary endpoint will be summarized by post-instillation timepoint using continuous summary 
statistics for the FAS. Paired t-tests will be used to test the statistical hypotheses. Each null hypothesis 
will be rejected if the corresponding two-sided p-value is less than 0.05. 
Sample Size Calculations 
A sample size of 30 subjects will have 80% power to detect a difference in means of 0.529 times the 
standard deviation of the paired differences, using a paired t-test with a 5% two-sided significance level. 
Summary of Known and Potential Risks and Benefits to Human Subjects 
Refer to MIEBO Prescribing Information (Appendix 3). 


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TABLE OF CONTENTS 
Title Page ........................................................................................................................................... 1 
Sponsor Approval Page ...................................................................................................................... 2 
Investigator’s Signature ...................................................................................................................... 3 
SPONSOR PERSONNEL .................................................................................................................. 4 
SYNOPSIS ........................................................................................................................................ 5 
TABLE OF CONTENTS ................................................................................................................. 10 
LIST OF ABBREVIATIONS ........................................................................................................... 13 
1 
INTRODUCTION ................................................................................................................... 15 
2 
STUDY OBJECTIVES ........................................................................................................... 16 
3 
CLINICAL HYPOTHESES..................................................................................................... 16 
4 
OVERALL STUDY DESIGN ................................................................................................. 16 
5 
STUDY POPULATION .......................................................................................................... 17 
  Number of Subjects (approximate) .......................................................................................... 17 
  Study Population Characteristics ............................................................................................. 17 
  Inclusion Criteria ...................................................................................................................... 17 
  Exclusion Criteria .................................................................................................................... 18 
  Withdrawal Criteria (if applicable) .......................................................................................... 19 
6 
STUDY PARAMETERS ......................................................................................................... 19 
  Efficacy Measures and Endpoints ............................................................................................ 19 
6.1.1 
Primary Efficacy Measure(s) and Endpoints ..................................................... 19 
6.1.2 
Secondary Efficacy Measure(s) and Endpoints ................................................. 19 
6.1.3 
Exploratory Efficacy Measure(s) and Endpoints ............................................... 19 
  Safety Measures ....................................................................................................................... 19 
7 
STUDY MATERIALS ............................................................................................................ 19 
  Study Treatment(s) .................................................................................................................. 19 
7.1.1 
Study Treatment ............................................................................................... 19 
7.1.2 
Instructions for Use and Administration ............................................................ 20 
  Other Study Supplies .............................................................................................................. 20 
8 
STUDY METHODS AND PROCEDURES ............................................................................ 20 
  Subject Entry Procedures......................................................................................................... 20 
8.1.1 
Overview.......................................................................................................... 20 
8.1.2 
Informed Consent ............................................................................................. 20 
8.1.3 
Washout Intervals ............................................................................................. 20 
8.1.4 
Procedures for Final Study Entry ...................................................................... 21 
  Concurrent Therapies ............................................................................................................... 21 
8.2.1 
Prohibited Medications/Treatments ................................................................... 21 
  Examination Procedures ........................................................................................................... 21 
8.3.1 
Procedures to be Performed at Each Study Visit ............................................... 21 
  Schedule of Visits, Measurements and Dosing ........................................................................ 23 
8.4.1 
Scheduled Visits ............................................................................................... 23 
8.4.2 
Unscheduled Visits ........................................................................................... 23 
  Compliance with Protocol ....................................................................................................... 23 
  Subject Disposition .................................................................................................................. 23 
8.6.1 
Completed Subjects .......................................................................................... 23 
8.6.2 
Discontinued Subjects ...................................................................................... 23 


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  Study Termination .................................................................................................................... 24 
  Study Duration ......................................................................................................................... 24 
  Monitoring and Quality Assurance .......................................................................................... 24 
9 
ADVERSE EVENTS .............................................................................................................. 24 
  Definition of Adverse Event (AE) ........................................................................................... 24 
9.1.1 
Assessment of Severity of Adverse Events ....................................................... 25 
9.1.2 
Assessment of Causality of Adverse Events ...................................................... 25 
  Serious Adverse Events........................................................................................................... 25 
9.2.1 
Expedited Serious Adverse Events ................................................................... 28 
9.2.2 
Pregnancy......................................................................................................... 28 
  General Guidelines for Reporting Adverse Events ................................................................... 29 
10 
STATISTICS .......................................................................................................................... 30 
 Assessment of Efficacy ........................................................................................................... 30 
10.1.1 Primary Efficacy .............................................................................................. 30 
10.1.2 Secondary Efficacy........................................................................................... 31 
10.1.3 Exploratory Efficacy ........................................................................................ 31 
10.1.4 Statistical Hypothesis Testing and Control of Multiplicity ................................ 31 
10.1.5 General Considerations ..................................................................................... 31 
 Assessment of Safety .............................................................................................................. 31 
10.2.1 Adverse Events ................................................................................................ 31 
10.2.2 Concomitant Medications ................................................................................. 31 
 Subject Disposition ................................................................................................................. 31 
 Demographics and Baseline Characteristics ............................................................................ 32 
 Protocol Deviations ................................................................................................................. 32 
 Compliance ............................................................................................................................. 32 
 Interim Analyses ..................................................................................................................... 32 
 Additional Statistical Considerations ....................................................................................... 32 
10.8.1 Analysis Population .......................................................................................... 32 
10.8.2 Sample Size Determination ............................................................................... 32 
10.8.3 Multiplicity Issues ............................................................................................ 32 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL CONSIDERATIONS, 
AND ADMINISTRATIVE ISSUES ........................................................................................ 33 
 Protection of Human Subjects.................................................................................................. 33 
11.1.1 Subject Informed Consent ................................................................................ 33 
11.1.2 Institutional Review Board (IRB) Approval ...................................................... 33 
 Ethical Conduct of the Study ................................................................................................... 33 
 Subject Confidentiality ............................................................................................................ 33 
 Documentation ........................................................................................................................ 34 
11.4.1 Retention of Documentation ............................................................................. 34 
 Labeling, Packaging, Storage, Accountability, and Return or Disposal of Investigational Product 
…………………………………………………………………………………………………...34 
11.5.1 Labeling/Packaging .......................................................................................... 34 
11.5.2 Storage of Investigational Product .................................................................... 34 
11.5.3 Accountability of Investigational Product ......................................................... 34 
11.5.4 Return or Disposal of Investigational Product ................................................... 34 
 Recording of Data on Source Documents and Case Reports Forms (CRFs) ............................. 34 
 Handling of Biological Specimens .......................................................................................... 35 
Publications ............................................................................................................................. 35 


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12 
REFERENCES ........................................................................................................................ 36 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
CFB 
Change from baseline 
CFS 
Corneal Fluorescein Staining 
CRF 
case report form 
DED 
Dry Eye Disease 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
IBI 
Inter-Blink-Interval 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
LBUT 
Lipid Break Up Time 
LLT 
Lipid Layer Thickness 
LMU 
Lipid Map Uniformity 
MALT 
Muco-Aqueous Layer Thickness 
MALTR 
rate of change of the MALT value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
Meibomian Gland Dysfunction 
NEI 
National Eye Institute 
NOV03 
Development name for perfluorohexyloctane (MIEBO) 
OD 
right eye 
OS 
left eye 
OU 
both eyes 
OSDI© 
Ocular Surface Disease Index 
PP 
per protocol 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
statistical analysis plan 


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SD 
standard deviation 
SDC 
Statistics and Data Corporation 
SOP 
standard operating procedure 
TEAEs 
Treatment-emergent Adverse Events 
TFBUT 
Tear Film Break-up Time 
VA 
Visual Acuity 


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1 INTRODUCTION 
Dry eye disease (DED) is a common ocular condition with approx. 18 million currently diagnosed with the 
disease in the US, and with many more people remaining undiagnosed (Farrand, et al. 2017; MarketScope 
2020). Typical clinical signs of DED include decreased tear fluid, tear film instability, and ocular surface 
damage with associated symptoms of dryness, grittiness, burning, stinging, light sensitivity, and blurred 
vision (Bartlett, et al. 2015; Craig, et al. 2017). Previously, DED was characterized into 2 main types, 
aqueous deficient (in which lacrimal secretion is reduced) or evaporative (in which evaporation of aqueous 
from the tear film is excessive) (Bron, et al. 2017; Craig, et al. 2017). It is now recognized that DED is on 
a continuum and that the most common cause of the disease is excessive evaporation due to conditions 
such as meibomian gland dysfunction (MGD), a reduced blink rate (for example due to long-term use of 
digital displays), certain drugs, contact lens use, and some eyelid disorders (Craig, et al. 2017). The most 
common cause of evaporative DED is MGD, which is present in approx. 9 out of 10 patients with the 
disease (Lemp, et al. 2012; Rabensteiner, et al. 2018; Badian, et al. 2021). MGD results in thinning of the 
tear film lipid layer leading to excessive evaporation of the underlying aqueous layer and associated tear 
film instability, hyperosmolarity, desiccation stress, and loss of mucin-producing goblet cells, which all 
cascade into a continuing cycle of inflammation and ocular surface damage (Baudouin, et al. 2016; Craig, 
et al. 2017). 
 
Current prescription DED therapies are aimed at reducing inflammation or increasing tear secretion but are 
not directly targeted at the main root cause of DED, namely excessive evaporation. Perfluorohexyloctane 
ophthalmic solution (PFHO; trade name MIEBO™; development name NOV03) is an FDA approved, 
water-free, non-steroidal, preservative-free eye drop indicated for treatment of the signs and symptoms of 
DED. PFHO belongs to a unique class of compounds known as semifluorinated alkanes which have low 
surface tension and amphiphilic properties due to a lipophobic/aerophilic fluorinated segment and a 
lipophilic hydrocarbon segment (Meinert and Roy 2000). PFHO is thought to act as a functional 
replacement for the lipid layer by spreading rapidly over the ocular surface to form a long-lasting, anti- 
evaporative barrier (Agarwal, et al. 2018; Krosser 2018; Borchman 2022). Therefore, PFHO may prevent 
excessive evaporation of the aqueous component of the tear film in patients with evaporative DED, thus 
reducing the signs and symptoms of DED as has been consistently demonstrated in both a Phase 2 study 
and 2 Phase 3 clinical studies (Tauber, et al. 2021; Sheppard 2022; Tauber, et al. 2022). 
 
To date, the effect of PFHO on inhibiting evaporation in vivo has not been demonstrated and there is 
limited available information regarding how PFHO modulates the lipid and aqueous tear film layers; in 
addition, demonstration of inhibition of evaporation by PFHO is currently limited to in vitro data. The 
Tear Film Imager (AdOM, Advanced Optical Technologies Ltd, Lod, Israel) combines spectrometry and 
imaging to quantitatively assess changes in the tear lipid and aqueous layers with nanometer resolution. 
There are 6 tear film parameters which are measured simultaneously with the TFI: 
 
1. MALT: the average Muco-Aqueous Layer Thickness in nanometer resolution 
2. MALTR: the rate of change of the MALT value in nm/sec, as measured in the steady state phase of 
a representative blink 
3. LLT: the average Lipid Layer Thickness in nanometer resolution 
4. LBUT: the Lipid Break Up Time (in sec) which strongly correlates to tear breakup time 
5. IBI: the average Inter-Blink-Interval (in sec). 
6. LMU: the average Lipid Map Uniformity measured on the Lipid map taken about 1 second after the 
blink which allows quantitation of the spatial variation of lipid across the cornea. 


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Several studies have been published which evaluated tear film parameters with the TFI. Cohen et al used 
the TFI to demonstrate that the distribution of lipid in eyes with DED is nonuniform and has more variance 
over the corneal surface as compared to normal eyes and hypothesized that this nonuniformity may be the 
cause of increased evaporation of the aqueous tear film layer in DED (Cohen, et al. 2020). In addition, the 
parameters of MALT and LBUT have been shown to be significantly thinner and shorter, respectively, in 
patients with DED vs controls (Segev, et al. 2020). Data from a recent study has also demonstrated 
correlation of specific tear film parameters with certain DED symptoms and/or signs (Arita, et al. 2022). 
Lastly, unpublished pilot data suggests that PFHO may decrease the MALTR and thus the rate of 
evaporation in a subject with evaporative DED. 
 
2 STUDY OBJECTIVES 
The primary objective is to test the hypotheses (twelve) that the effects of a single instillation of PFHO in 
the study eye on the thickness and evaporation rate of the mucus-aqueous layer of the tear film at six time 
points between 5 minutes and 4-hours (5±1 min, 15±2 min, 30±2 min, 60±5 min, 120±10 min, 240±10 
min) after instillation are nominally statistically significant in adults with established currently untreated 
bilateral dry eye disease associated with meibomian gland dysfunction who are not recent users of contact 
lenses or any medication that could affect ocular dryness. 
 
 
 
 
3 CLINICAL HYPOTHESES 
It is hypothesized that PFHO will increase MALT and decrease MALTR in a population of subjects with 
dry eye disease associated with MGD. 
 
4 OVERALL STUDY DESIGN 
This is a pilot, open label, single arm study. 
The study will consist of 2 study visits: a Screening Visit to verify subjects are eligible to participate and an 
Assessment study visit to evaluate tear film parameters at baseline and over approx. 4 hours following a 
single instillation of PFHO (Figure 1). 
At Visit 1, the subjects will complete the informed consent process followed by a screening visit to determine 
the presence of dry eye and associated MGD, which will include slit-lamp exam, visual acuity (VA), IOP, 
MGD assessment, Schirmer test, TBUT, CFS, OSDI. At Visit 2, a slit lamp examination will be performed. 
After 20 min, a baseline examination will be conducted by performing a Tear Film Imager assessment in the 
study eye (tear film parameters measured twice 20-40 min apart; study eye = worst CFS eye at baseline). 
The study eye drop will then be applied to both eyes. Tear film imager assessments will then be performed 
in the study eye at multiple time points up to 4 hours post-instillation as shown in Figure 1. 


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Figure 1: Study Design Schematic 
 
 
 
5 STUDY POPULATION 
 
Number of Subjects (approximate) 
Approximately 50 subjects will be screened in order to enroll approximately 30 subjects. 
 
 
Study Population Characteristics 
Subjects of at least 18 years of age of either sex and any race, with a diagnosis of dry eye disease, who 
meet all of the inclusion criteria and none of the exclusion criteria. 
 
Inclusion Criteria 
General/Ocular Inclusion Criteria 
 
1. Will be at least 18 years of age at the time of consent. 
2. Able to provide written voluntary informed consent. 
3. Have a subject-reported history of DED in both eyes for at least 6 months prior to Visit 1. 
4. Have Tear film break-up time (TFBUT) <10 sec at Visit 1. 
5. Have Meibomian Gland Dysfunction (MGD) defined as total MGD score ≥ 3 (secretion of 5 central 
glands on lower eyelid will be evaluated, each will be scored from 0-3; 0 = normal, 1 = 
thick/yellow, whitish, particulate 2 = paste; 3 = none/occluded; total score will range from 0-15) at 
Visit 1. 
6. Have a total corneal fluorescein staining score of ≥2 and ≤11 (i.e. sum of inferior, superior, central, 
nasal, and temporal) according to the National Eye Institute (NEI) scale at Visit 1. 
7. Have at least one eye that satisfies all criteria for 4-6 above at Visit 1. 
8. Is able to fix his/her gaze for a minute, i.e. can see the fixation target and with no nystagmus 
9. Is able and willing to follow instructions, including participation in all trial assessments and visits. 


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Exclusion Criteria 
General/Ocular Exclusion Criteria 
1. Have any clinically significant ocular surface slit-lamp findings at Visit 1 and Visit 2 and/or in the 
opinion of the Investigator had any findings that may have interfered with trial parameters, 
including 
a. history of eye trauma 
b. history of Stevens-Johnson syndrome 
c. active blepharitis or lid margin inflammation 
d. DED secondary to scarring, irradiation, alkali burns, cicatricial pemphigoid, or destruction 
of conjunctival goblet cells (as with vitamin A deficiency). 
e. abnormal lid anatomy that caused incomplete eyelid closure 
f. corneal epithelial defect or significant confluent staining or filaments 
g. abnormal cornea shape (keratoconus) 
h. history of herpetic keratitis. 
i. has a pterygium in either eye. 
j. ocular or periocular rosacea that in the judgement of the Investigator interfered with the trial 
2. Has used any topical ocular steroids treatments, prescription dry eye therapy including varenicline 
nasal spray, or topical anti-glaucoma medication within 60 days prior to Visit 1. 
3. Have had a LipiFlow procedure within 1 month prior to Visit 2. 
4. Have received a permanent punctum plug within 3 months (6 months for dissolvable punctum 
plugs) prior to Visit 2. Have removed a permanent punctum plug within 1 month prior to Visit 2. 
5. Have used any eye drops (prescription or artificial tears) and/or TrueTearTM device (intranasal tear 
neurostimulator) within 24 hours before Visit 2. 
6. Have active ocular allergies or ocular allergies that are expected to be active during the trial period. 
7. Have worn contact lenses within 1 month of Visit 1 or anticipate using contact lenses during the 
trial. 
8. Have undergone intraocular surgery or ocular laser surgery within the previous 6 months or had any 
planned ocular and/or lid surgeries over the trial period. 
9. Have an active ocular or systemic infection (bacterial, viral, or fungal), including fever requiring 
treatment with antibiotics. 
10. Is a woman who was pregnant, nursing or planning a pregnancy. 
11. Is a woman of childbearing potential who is not using an acceptable means of birth control; 
acceptable methods of contraception included: 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 could have been regarded as an adequate method of birth control; 
however, if the subject becomes sexually active during the trial, she must agree to use adequate 
birth control as defined above for the remainder of the trial. 
12. Has an uncontrolled systemic disease in the opinion of the Investigator will interfere with the trial. 
13. Has a known allergy and/or sensitivity to the investigational drug or saline components. 
14. Has used any oral medications known to cause ocular drying (eg, antihistamines, antidepressants, 
etc.) on a non-stable regimen within 1 month prior to Visit 1 or is expected to be unstable during the 
trial. 
15. Have taken isotretinoin (e.g. Accutane, Myorisan, Claravis, Amnesteem) within 6 months of Visit 1 
16. Has corrected VA worse than or equal to logarithm of the minimum angle of resolution (LogMAR), 
+0.7 as assessed with Early Treatment Diabetic Retinopathy Study (ETDRS) charts in both eyes at 
Visit 1. 


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17. Is currently enrolled in an investigational drug or device study or had used an investigational drug 
or device within 60 days of Visit 2. 
 
Withdrawal Criteria (if applicable) 
Subjects may voluntarily withdraw from the study at any time. 
Additionally, subjects may be discontinued for safety reasons as determined by the investigator (see 
Section 8.6.2). 
 
6 STUDY PARAMETERS 
 
Efficacy Measures and Endpoints 
6.1.1 Primary Efficacy Measure(s) and Endpoints 
• Change from baseline in mucus-aqueous layer thickness (MALT) and thinning rate (MALTR) for 
study eyes at 5±1 min, 15±2 min, 30±2 min, 60±5 min, 120±10 min, and 240±10 min following 
instillation of NOV03 
6.1.2 
 
 
 
 
 
 
 
 
 
 
 
Safety Measures 
• Adverse Events (AEs; reported, elicited and observed) 
 
7 STUDY MATERIALS 
 
Study Treatment(s) 
7.1.1 Study Treatment 
PFHO drug product is a thin, clear, preservative-free ophthalmic drop (see Table 1). PFHO 
must be stored in a secure area accessible only to the investigator or pharmacist and his/her 
designees. PFHO must be stored at room temperature under temperature- monitored 
conditions and must not be refrigerated. 


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Table 1 
Active Investigational Product 
Investigational Product 
Product code: 
NOV03 (MIEBO™) 
Chemical name: 
Perfluorohexyloctane (PFHO) 
Molecular formula: 
C14H17F13 
Dosage form: 
3 mL ophthalmic solution 
Unit dose: 
11 µL drop size; 100% perfluorohexyloctane 
Route of administration: 
Topical ocular administration 
Physical description: 
Colorless and clear ophthalmic solution 
Excipients: 
None 
Manufacturer: 
 
 
 
7.1.2 Instructions for Use and Administration 
• At Visit 2, a designated clinical staff member will instill 1 drop of the investigational product into 
each eye: 
 
 
Other Study Supplies 
• Questionnaires, Urine Pregnancy Tests, sterile cotton-tipped swab (for MGD assessment), 
Schirmer’s test strips, sodium fluorescein. 
 
8 STUDY METHODS AND PROCEDURES 
 
Subject Entry Procedures 
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be considered for entry into this study. 
8.1.2 Informed Consent 
Following identification of a potential subject, the Investigator (or designee) will explain the purpose of the 
study, procedures, risks/benefits, and subject responsibilities to the potential subject. The subject’s 
willingness and ability to meet the follow-up requirements of the study will be determined. If the subject 
chooses to participate in the investigation, written informed consent will be obtained. The subject and the 
person obtaining written consent will sign and date the IRB-approved ICF, at which point the subject is 
considered part of the study population. The original signed document will be retained in the subject 
records, and a copy will be provided to the subject. In addition, the applicable privacy regulation 
requirements must be met. 
8.1.3 Washout Intervals 
Subjects will adhere to the following medication washout intervals during the period indicated prior to 
Visit 1 or 2 as indicated and will refrain from using these medications during the study: 
24 Hours 


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Artificial tears, topical ocular prescription eye drops, True Tear device, lid scrubs, lid wipes, 
warm compresses within 24 hours of Visit 2 (Assessments) 
 
1 Month 
 
• contact lenses within 30 days of Visit 1 (Screening) 
• oral medications known to cause ocular drying (e.g. antihistamines, antidepressants etc) on a 
non-stable regimen with 30 days of Visit 1 (Screening) 
• Lipiflow within 30 days of Visit 2 (Assessment) 
• Removed a punctal plug within 30 days on Visit 1 (Screening) 
2 Months 
 
• Topical steroids, cyclosporine, lifitegrast, serum tears, glaucoma medication within 60 days 
of Visit 1 (Screening) 
3 Months 
 
• Received a permanent punctum plug within 90 days of Visit 2 (Assessment) 
 
6 Months 
• Received or removed a dissolvable punctum plug within 6 months of Visit 2 (Assessment) 
• Have taken isotretinoin (e.g. Accutane, Myorisan, Claravis, Amnesteem) within 6 months of 
Visit 1 (Assessment) 
 
 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to be enrolled in 
the study. 
 
  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 case report form (CRF) 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 
Refer to Section 8.1.3 for a complete list 
 
Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit 
Refer to Appendix 2 for details on the ocular assessments. 


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8.3.1.1 VISIT 1 (Day -14 to Day -1): Screening/ Informed Consent/ Eligibility 
 
• Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment and/or study visit 
procedures, the study will be discussed with each subject and subjects wishing to participate must 
give written informed consent and sign a HIPAA form. 
In the event that a subject has a medical condition, medication/contact lens washout, or needs to 
speak with the Investigator prior to Visit 1, the subject will be given an informed consent form. 
Medical/medication history, demographics, and inclusion/exclusion review may be performed at the 
time of informed consent signing prior to Visit 1, but must be confirmed at Visit 1. 
• Demographic data and medical/medication/ocular and non-ocular history: Collect and record all 
demographic data, medical history, any medications, and any underlying condition(s). Current 
underlying conditions, including those that began within the last 30 days, which may have been 
resolved before screening must be recorded. Record any medications the subject is taking, as well 
as those the subject may have taken but discontinued within 60 days prior to Visit 1. 
 
• Review of Inclusion/Exclusion Criteria: A review of protocol inclusion and exclusion criteria will 
be confirmed for each subject. 
• Urine Pregnancy Test (for females of childbearing potential): Females of childbearing potential must 
have a negative urine pregnancy test to continue in the study and must agree to use an acceptable 
method of contraception throughout participation in the study. 
• 
Ocular Surface Disease Index (OSDI©) questionnaire 
 
• 
Visual acuity (ETDRS) 
 
• 
Slit-Lamp biomicroscopy 
 
• 
Tear Film Break-up Time (TFBUT) 
 
• 
Fluorescein staining (NEI scale)  
 
• 
Meibomian gland assessment (MGD score) (wait 5 min prior to start of Schirmer`s test) 
 
• 
Schirmer’s test I (without anesthesia)  
 
• 
Intraocular pressure 
 
• Adverse Event Query  
 
• Schedule Visit 2: Qualifying subjects will be scheduled to return to the office for Visit 2. 
 
 
8.3.1.2 VISIT 2 (Day 1) 
 
• Update of Medical/Medication History 
• 
Slit-Lamp biomicroscopy (wait ~20 min prior to TFI baseline measurements) 


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• Baseline Tear Film Imager assessments (2 measurements made 20-40 min apart) 
• Instillation of study drug 
• Post-instillation Tear Film Imager assessments (at 5, 15, 30, 60, 120 and 240 min following PFHO 
instillation) 
 
• Adverse Event Query  
• Study Exit 
 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
If a subject is discontinued at a scheduled study visit, the remaining assessments should be captured on the 
Unscheduled Visit/Early Exit Visit pages of the Source Document and corresponding CRF. 
8.4.2 Unscheduled Visits 
For Unscheduled Visits, the reason for the visit should be clearly documented on the appropriate CRF, 
including findings from all evaluations that are completed. 
 
These visits may be performed to ensure subject safety. All information gathered at unscheduled visits 
should be recorded on the Unscheduled Visit/ Early Exit Visit pages of the Source Document and 
corresponding CRF. 
 
 
Compliance with Protocol 
Subjects who are inappropriately enrolled may be discontinued from the study. The reason for such 
discontinuation will be recorded as “protocol violation” in the source document and on the appropriate 
page in the CRF. 
 
Site staff will review concomitant medication use at each visit. Any new medication (or) changes in 
existing concomitant medication use will be recorded in the source document and on the Concomitant 
medication CRF. 
 
 
Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• 
subject request/withdrawal 
• 
AEs 
• 
protocol violations 


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• 
administrative reasons (e.g., inability to continue, lost to follow up) 
• 
sponsor termination of study 
• 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made to the sponsor and 
will be clearly documented on the CRF. 
 
Study Termination 
The study may be stopped at any time by the investigator or the sponsor with appropriate notification. 
 
 
Study Duration 
This trial consists of 2 office visits over a period of approximately 2 weeks. 
 
 
Monitoring and Quality Assurance 
Audits of clinical research activities in accordance with the Bausch + Lomb’s internal Standard Operating 
Procedures (SOPs) to evaluate compliance with the principles of GCP may take place. A regulatory 
authority may also wish to conduct an inspection (during the study or after its completion). If an inspection 
is requested by a regulatory authority and/or IRB, the Investigator must inform Bausch + Lomb 
immediately that this request has been made. 
 
9 ADVERSE EVENTS 
 
Definition of Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a subject participating in a clinical study, which 
does not necessarily have a causal relationship with the study product/procedure. Therefore, an adverse 
event includes: 
• Any unfavorable and/or unintended sign (including an abnormal laboratory finding), symptom, or 
disease onset, that occurs at any time between the signing of the ICF and study exit, without any 
judgement about causality (i.e., whether or not it is considered to be related to the study product) 
• Exacerbation, worsening, or progression of a pre-existing illness, including an increase in severity, 
frequency, and/or duration of a pre-existing episodic event or condition 
• Events occurring from drug overdose (accidental or intentional), drug abuse or misuse, drug 
hypersensitivity, drug extravasation, drug interactions, drug dependency, events occurring from 
drug withdrawal and medication errors 
• A condition detected or diagnosed after study product administration even though it may have been 
present prior to the start of the study 
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after the first dose 
of study drug, or that worsened following administration of study drug. 
An AE does not include the following: 


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• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) as event 
terms; the condition that led to the procedure is the AE if it meets the definition of an AE. 
•  Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
cosmetic elective surgery; and social and/or convenience admissions). 
Symptoms associated with disease, which are consistent with the subject’s usual clinical course; unless the 
subject experiences worsening of their symptom(s) or the symptom(s) meet the criteria for an SAE. 
 
9.1.1 Assessment of Severity of Adverse Events 
The severity of an AE will be graded as follows: 
Mild 
Awareness of a sign or symptom but is easily tolerated, 
requires no treatment, and does not interfere with subject’s 
daily activities 
Moderate 
Low level of concern to the subject and may interfere with 
daily activities but can be relieved by simple therapeutic 
care. 
Severe 
Interrupts the subject’s daily activity and requires 
systemic therapy or other treatment 
 
9.1.2 Assessment of Causality of Adverse Events 
The relationship of an AE to the study product will be assessed using the following guidelines, based upon 
available information: 
 
Related 
There is at least a reasonable possibility that the AE/SAE 
is related to the study drug. Reasonable possibility means 
that there is evidence to suggest a causal relationship 
between the drug and the AE. 
Not Related 
There is little or no reasonable possibility that the 
AE/SAE is related to the study drug. This assessment 
implies that the AE/SAE has little or no temporal 
relationship to the study drug and/or a more likely or 
certain alternative etiology exists. 
 
Rationale MUST be provided for any “not related” assessment and is recommended for “related” 
assessments. 
 
Serious Adverse Events 
An AE is considered “serious” if it meets at least one of the following criteria. The event: 
• Results in death 


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• Is life threatening (places the subject at immediate risk of death) 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization NOTE: The term 
“hospitalization” refers to admission to a hospital as an in-patient for more than 24 hours. 
Therefore, an adverse event would meet the SAE criterion of “requires hospitalization” only if the 
event necessitated admission to a health care facility for longer than 24 hours. Elective 
hospitalization for an intervention that was already planned before inclusion of the subject in the 
study, hospitalization solely for the purpose of diagnostic tests (even if related to an AE), hospital 
admission for social circumstances, and admission to a day-care facility may not constitute 
sufficient grounds to be considered an SAE. 
Cases in which subjects are retained in the emergency room for more than 24 hours but not 
admitted for medical care should be evaluated individually, because the criterion “otherwise 
medically significant” may apply (see below). 
• Results in persistent or significant disability/incapacity 
NOTE: The term “disability” means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance (e.g., uncomplicated headache, influenza, or sprained ankle) that may transiently 
interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Is considered otherwise medically significant, as determined by the PI or medically qualified sub- 
investigator 
NOTE: The term “medically significant” refers to important medical events that may not immediately 
be life threatening or result in death or hospitalization, but, based upon appropriate medical judgment, 
they jeopardize the subject or require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition of an SAE. 
Examples of such medically significant events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Spontaneous abortion, elective abortion and ectopic pregnancy will be considered SAEs and must be reported 
to the sponsor within 24 hours of awareness of the event. 
Subjects will be withdrawn from the study if an SAE is identified and thought to be related to the study drug. 
The investigator is responsible for the reporting of all SAEs. 
Within 24 hours following the investigator’s knowledge of an SAE, the investigator must: 
• Report the SAE to the sponsor/designee. 
All SAEs occurring between screening and 30 days after the last administered dose of study drug 
(inclusive) must be reported to the sponsor/designee, independent of the circumstance or suspected 
cause, and regardless of the relationship to the study drug or protocol, within 24 hours from the time 
the event was reported to the investigator. For events occurring beyond the 30-day period after the 
last application of study drug, or for any timeframe greater than 30 days deemed medically 


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significant, only SAEs considered related to the study drug should be reported promptly to the 
sponsor. 
If the subject dies during participation in the study or during recognized follow-up period, and if 
cause of death is not available within the 24-hour reporting period, “death” must be reported as an 
SAE term to meet the timelines. Cause of death must be actively queried and submitted as a follow- 
up report. 
• Fax or email a completed Serious Adverse Event Report to the following designees: 
Sponsor Contact: 
Email: drugsafety@bausch.com 
cc: clinicalsafety@bausch.com 
Fax: +1-585-510-5552 
 
Include copies of all confirmatory examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the subject's identity is protected 
(personal identifiers are redacted), and the date and subject identifier in the clinical trial (i.e., 
subject number) are clearly visible on every page/copy of source document provided to the sponsor. 
For laboratory results, include the laboratory normal ranges. 
• Investigators should not wait to receive additional information before notifying the sponsor of an 
SAE. If only limited information is initially available, follow-up reports are required. 
Within 48 hours following the investigator’s knowledge of an SAE, the investigator must: 
• Enter the information related to the SAE in the appropriate sections of the CRF. 
• Send notification of the SAE to the monitoring team after investigator approval of the CRF 
All further data updates should be recorded in the CRF within one working day of knowledge of this 
additional information. Send notification of the updated SAE information to the monitoring team after 
investigator approval of the CRF. 
Additional documentation (e.g., laboratory data, concomitant medication, subject status, etc.), should 
be sent by fax or e-mail to the monitoring team within one working day of knowledge of this 
information. Care should be taken to ensure that the subject's identity is protected (personal identifiers 
are redacted) and the date and subject identifier in the clinical trial (i.e., subject number) are clearly 
visible on every page/copy of source document that is provided to the monitoring team. For laboratory 
results, include the laboratory normal ranges. 
After the EOS visit, the investigator does not need to actively monitor subjects for new SAEs. 
However, if the investigator becomes aware of a new or previously unreported serious adverse event 
within 30 days after the last investigational drug instillation, the event should be reported to the 
sponsor/designee within 24 hours of learning of the event. If the investigator becomes aware of a new 
or previously unreported SAE after 30 days from the last investigational drug instillation, only SAEs 
considered related to the study drug should be reported to the sponsor within 24 hours of the 
investigator’s knowledge of the event. Serious adverse events reported outside of the protocol-required 
reporting period will be captured within the safety database as clinical trial SAE Report Form cases for 
the purposes of expedited reporting. 


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9.2.1 Expedited Serious Adverse Events 
Any suspected unexpected serious adverse event considered related to the study drug may warrant 
expedited reporting. In addition, any unexpected SAE related to a subject’s participation in the study (or 
related to the conduct of the study), regardless of whether or not the study drug was administered, will be 
evaluated by Global Pharmacovigilance and Risk Management to determine if expedited reporting is 
required. For example, an unexpected, severe SAE that could be associated with the study procedures and 
could modify the study conduct requires expedited reporting. 
Each expedited safety report will routinely include a brief cover memorandum, the completed MedWatch 
Form FDA 3500A, a clinical analysis of the event with any similar events that have occurred with the 
product, and any additional pertinent information recommended by the study medical monitor. Once the 
report is compiled, the study center’s investigator must submit the expedited safety report to the local 
IRB/IEC within the required reporting timeframe. Follow-up reports should be submitted when requested 
or when pertinent information becomes available. The principal investigator must retain a complete copy of 
each expedited safety report as it was submitted to the IRB/IEC. It is important that the principal 
investigator review these expedited reports, as they contain safety information that may be relevant to each 
of the participating subjects. 
 
9.2.2 Pregnancy 
All female subjects of childbearing potential and male subjects with female partners of childbearing 
potential must use an effective method of birth control during the course of the study, in a manner such that 
risk of contraceptive failure is minimized. Abstinence is allowed as a birth control method. Before 
enrolling a female subject of childbearing potential or a male subject with a female partner of childbearing 
potential, the investigator must review the following information about study participation: 
 
• Informed consent requirement 
• Contraceptives in current use 
By signing the informed consent form, the investigator or designee asserts that he/she has discussed this 
information with the subject and provided appropriate counseling. Following the review of this 
information, the subject must sign the informed consent form to enroll in the study. During the study, all 
subjects should be instructed to contact the investigator immediately if they suspect that they or their 
partners might be pregnant (e.g., missed or late menstrual period). 
 
If a subject or investigator suspects that the subject may be pregnant prior to treatment, the study drug must 
be withheld until the results of laboratory pregnancy testing are available. If pregnancy is confirmed, the 
subject is considered to be a screen failure, must not continue in the study, and must not receive study drug. 
If pregnancy is suspected while the subject is receiving study treatment, the study drug must immediately 
be withheld until the result of pregnancy testing is known. If pregnancy is confirmed, the study drug will 
be permanently discontinued, and the subject and neonate will be followed until 30 days after the 
pregnancy comes to term. A Pregnancy Report form will be submitted to the sponsor, both when 
pregnancy is confirmed, and 30 days after the delivery date. Information provided on the Pregnancy 
Report Form must include the outcome of the pregnancy and any complications occurring during the 
pregnancy or the delivery. 
 
If a subject is withdrawn from the study and is found to be pregnant within 30 days of withdrawal, the 
subject and neonate will be followed until 30 days after the pregnancy comes to term. 


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All confirmed pregnancies must be immediately reported to the sponsor/designee and medical monitor on a 
Pregnancy Report form within 24 hours of the investigator’s awareness of the pregnancy. If a pregnancy is 
associated with an SAE, an SAE report form should also be submitted to the sponsor/designee and medical 
monitor within 24 hours of the investigator’s awareness. Abnormal pregnancy outcomes (e.g., spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
Completed SAE Report Forms and completed Pregnancy Report Forms should be transmitted to the 
sponsor/designee and the medical monitor using the contact information provided in Section 9.2 above. 
 
If/when the investigator becomes aware of any new information regarding a pregnancy, the 
sponsor/designee and medical monitor should be notified of these updates as soon as the new information 
becomes available. Updates should be documented on a Pregnancy Report Form and sent by fax or email 
using the contact information provided above. The report should be marked as a follow-up report” and 
should include the updated status of the pregnancy. The original Pregnancy Report Form is not to be 
altered. 
 
 
General Guidelines for Reporting Adverse Events 
It is the responsibility of the investigator to document all AEs that occur during the course of the study. 
Throughout the study, efforts will be made by the investigator to remain alert to possible AEs. The period 
of observation for collection of AEs extends from the time the subject gives informed consent until the last 
study visit or discontinuation from the study. The first concern will always be the safety of the subject, and 
appropriate medical intervention will be made. 
The AEs should be documented as a single medical diagnosis. When this is not possible, the AE should be 
documented in terms of signs and/or symptoms observed by the investigator or reported by the subject at 
each study visit. Each AE which appears to be independent of any prior event will be reported separately. 
All AEs occurring after the subject signs the informed consent through the last study visit must be reported, 
regardless of whether or not the AEs are considered drug-related. All AEs, whether in response to a query, 
observed by the study site personnel, or reported spontaneously by the subject, will be recorded. Any AEs 
deemed related to treatment reported or observed at the final study/treatment visit will be followed until 
stabilization or resolution (or up to 30 days after final study visit). 
At each visit during the study, the subject will be assessed for the occurrence of new and ongoing AEs. 
Tolerability signs and symptoms that result in the subject’s requiring a concomitant therapy, interruption of 
treatment, or discontinuation from the study will be reported as an AE. The following data will be collected 
on all AEs and recorded on the appropriate CRF: 
• Event name (diagnosis preferred, if unknown, record the signs/symptoms) 
• Onset date and end date 
• Maximum intensity (severity) 
• Seriousness 
• Action taken regarding study drug 
• Corrective treatment/therapy, if given 
• Outcome 


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• Resolution 
The investigator will also provide an assessment of the causal relationship to the study drug (for pre- 
treatment AEs, causality is “not related”). Rationale MUST be provided for any “not related” assessment 
and is recommended for “related” assessments. 
All AEs must be reported regardless of whether the AEs are considered drug-related. 
In order to ensure the safety of the subjects, the investigator should take appropriate measures to follow all 
subjects with adverse events until clinical recovery is complete, progression has been stabilized, the subject 
is lost to follow-up, or until death. This may result in the need for observations to continue beyond the last 
planned protocol specified visit, and additional investigations may be requested by the monitoring team. 
If a subject requires further follow-up of ongoing AEs upon discontinuation or completion of the study, the 
Investigator should schedule post-study follow-up visits, as necessary. 
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs (or SAEs, if applicable) 
only if at least one of the following apply: 
• the result is clinically significant 
• the subject is symptomatic 
• the subject requires either corrective treatment or consultation 
• the lab result, vital sign, or ECG abnormality leads to study drug discontinuation or dose 
modification 
• the event fulfills a criterion for an SAE 
In addition, the investigator’s assessment of causality will be recorded. 
Vital sign abnormalities are to be recorded as AEs (or SAEs, if applicable) only if they are clinically 
significant (for example: are symptomatic, requiring corrective treatment, leading to discontinuation or 
fulfilling a seriousness criterion). 
 
10 STATISTICS 
 
Assessment of Efficacy 
Efficacy evaluations will be completed using the Full Analysis Set. 
10.1.1 Primary Efficacy 
For each primary endpoint at each post-instillation timepoint, the null hypothesis (H0) is that the mean 
change from baseline (δ) is zero. The alternative hypothesis is that the mean change from baseline is not 
zero. 
𝐻𝐻0: 𝛿𝛿 = 0 
𝐻𝐻1: 𝛿𝛿 ≠ 0 
MALT and MALTR will be summarized using continuous summary statistics by time point (baseline, 5 
minutes, 15 minutes, 30 minutes, 1-, 2-, and 4 hours). Change from baseline (post-instillation minus 
baseline) at each post instillation time point will be summarized using continuous summary statistics. 
Paired t-tests will be used to test the statistical hypotheses. 


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10.1.2 Secondary Efficacy 
This section is not applicable because there are no secondary efficacy endpoints. 
10.1.3 Exploratory Efficacy 
The exploratory endpoints will be analyzed in the same manner as the primary efficacy endpoints. 
10.1.4 Statistical Hypothesis Testing and Control of Multiplicity 
Due to clinical considerations, the 36 statistical tests will not be adjusted for multiplicity. The p-values and 
any conclusions of statistical significance will be considered nominal. 
10.1.5 General Considerations 
Quantitative variables will be summarized descriptively using the number of subjects (n), mean, median, 
standard deviation, minimum, and maximum. Qualitative variables will be summarized using counts and 
percentages. 
All efficacy analyses will use a two-sided alpha = 0.05 test unless otherwise stated and corresponding 2- 
sided 95% confidence intervals (CIs) will be presented as applicable. 
For efficacy and non-ocular safety analyses, the unit of analysis will be the subject. In the cases where 
assessments are recorded for each eye, the study eye and fellow eye will be summarized separately and a 
mean across all eyes will also be calculated. 
 
Adverse events will also be summarized at the subject level; if an AE occurs in either or both eyes, the 
subject will be counted as having the AE. For other ocular safety analyses the unit of analysis will be the 
eye, with summaries showing results for the study eye and the fellow eye separately. 
 
 
Assessment of Safety 
The following safety variables will be recorded: 
 
• Adverse Events (AEs; reported, elicited and observed) 
10.2.1 Adverse Events 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and percentages of 
treatment-emergent adverse events (TEAEs) will be summarized at the subject level by system organ class 
and preferred term for all TEAEs, treatment related TEAEs, and serious TEAEs. An AE is treatment 
emergent if it occurs or worsens after the first dose of study medication. Similar summaries will be 
presented for all TEAEs by maximal severity. Separate summaries will be performed for ocular and non- 
ocular AEs. 
10.2.2 Concomitant Medications 
All previous concomitant medications will be classified based on terminology from the WHO Drug 
Dictionary. Previous therapies and concomitant medications data will be presented in data listings. 
 
 
Subject Disposition 
Subject disposition will be presented in terms of the numbers and percentages of subjects who completed 
the study and discontinued from the study. 


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The number and percentage of subjects who prematurely discontinue from the study and the reasons for 
study discontinuation will be summarized. 
 
 
Demographics and Baseline Characteristics 
Subject demographics including age, sex, ethnicity, race, and baseline characteristics will be summarized 
using the appropriate descriptive statistics. 
 
Protocol Deviations 
All protocol deviations will be reported to the sponsor and recorded throughout the study. A tabulation of 
protocol deviations (including categorizations of major and minor) will be presented. 
Important protocol deviations leading to exclusion from the Per-Protocol Population will include the 
following. 
• Ineligibility 
• Missing primary endpoint data at any time point at Visit 1 
• Use of any prohibited medication potentially affecting the primary endpoint at Visit 1 
 
 
 
Compliance 
Compliance will not be evaluated in this study since the site will administer the drop. 
 
 
Interim Analyses 
There are no interim analyses planned for this study. 
 
 
Additional Statistical Considerations 
10.8.1 Analysis Population 
• Full Analysis Set (FAS): The FAS will consist of all subjects who are instilled with study 
drug. 
• Per Protocol Set (PP Set): The PP Set will consist of FAS subjects with no protocol 
deviations expected to affect the evaluability of efficacy. 
10.8.2 Sample Size Determination 
A sample size of 30 subjects will have 80% power to detect a difference in means of 0.529 times the standard 
deviation of the paired differences, using a paired t-test with a 5% two-sided significance level. 
10.8.3 Multiplicity Issues 
The probability of at least one type 1 error will be approximately 79% under the universal null hypothesis 
if the 36 endpoints are independent. 


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11 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 adhered to. 
 
 
Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are initiated. Signed and 
dated written informed consent must be obtained from each subject and/or from the subject’s parent or 
legal guardian prior to enrollment into the study. If the subject is under the legal age of consent, the consent 
form must be signed by a legal guardian or as required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by the sponsor and receive approval/favorable 
opinion from an IRB/IEC prior to their use. If the consent form requires revision (e.g., due to a protocol 
amendment or significant new safety information), it is the investigator’s responsibility to ensure that the 
amended informed consent is reviewed and approved by B+L prior to submission to the governing 
IRB/IEC and that it is read, signed and dated by all subjects subsequently enrolled in the study as well as 
those currently enrolled in the study. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 56.103). The 
investigator must obtain appropriate IRB approval before initiating the study and re-approval at least 
annually. 
Only an IRB/IEC 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. 
Anonymized TFI measurement data will be analyzed by AdOM. 
Monitors, auditors and other authorized representatives of the sponsor, the IRB/IEC approving this study, 
the FDA, the DHHS, other domestic government agencies, and other foreign regulatory agencies will be 
granted direct access to the subject’s original medical and study records for verification of the data and/or 
clinical trial procedures. Access to this information will be permitted to the aforementioned individuals to 
the extent permitted by law. 


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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 EKGs. 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. 
 
 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
11.5.1 Labeling/Packaging 
The investigational materials will be packaged and labeled in a manner consistent with the study design. 
They will be labelled according to the local regulatory requirements 
11.5.2 Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her designees. The IP will 
be administered only to subjects entered into the clinical study, in accordance with the conditions specified 
in this protocol. 
11.5.3 Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or his/her named sub-investigator(s), and is to 
only be used in accordance with this protocol. The IP must only be distributed to subjects properly 
qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the sponsor on the Product 
Accountability Log. 
11.5.4 Return or Disposal of Investigational Product 
All IP will be returned to the sponsor at the end of the study. 
 
 
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, 


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legible, contemporaneous, and original. Recorded datum should only be corrected in a manner that does not 
obliterate, destroy, or render illegible the previous entry (e.g., by drawing a single line through the incorrect 
entry and writing the revision next to the corrected data). An individual who has corrected a data entry 
should make clear who made the correction and when, by adding to the correction his/her initials as well as 
the date of the correction. 
 
 
Handling of Biological Specimens 
Not Applicable. 
 
 
 
 
 
 
 
 
 
 
 


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