Clinical trial NCT04567329
Conditions: Dry Eye Disease
Sponsor: Bausch & Lomb Incorporated
Start date: 2020-11-18; Completion date: 2021-08-30
Enrollment: 620 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this trial are to assess the efficacy, safety, and tolerability of NOV03 ophthalmic solution in comparison to a saline control for the treatment of the signs and symptoms of Dry Eye Disease (DED) associated with Meibomian Gland Dysfunction (MGD).

Detailed description:

Arms: arm 1: 100% perfluorohexyloctane 4 times daily (QID) arm 2: 0.6% sodium chloride solution 4 times daily (QID)
Interventions: intervention 1: NOV03 intervention 2: Saline Solution
Intervention descriptions: intervention 1: 100% perfluorohexyloctane intervention 2: 0.6% sodium chloride solution

Protocol documents:
SAP_002.pdf: 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
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SAP Version History/Summary of Changes 
 
Version/Date 
Summary of Changes 
1.0/17 December 2020 
Initial Issuance of Document 
 
 
 
 
 
 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
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2 
TABLE OF CONTENTS 
 
1 
TITLE/SIGNATURE PAGE ................................................................................... 1 
SAP Version History/Summary of Changes .............................................................................. 2 
2 
TABLE OF CONTENTS ........................................................................................ 3 
2.1 
Table of Tables .................................................................................................... 6 
2.2 
Table of Figures .................................................................................................. 6 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................... 7 
4 
INTRODUCTION .................................................................................................. 9 
5 
TRIAL OBJECTIVES .......................................................................................... 12 
5.1 
Primary Objective ............................................................................................. 12 
5.2 
Secondary Objectives ....................................................................................... 12 
6 
INVESTIGATIONAL PLAN ............................................................................... 13 
6.1 
Overall Trial Design ......................................................................................... 13 
6.1.1 
Trial Design Diagram ................................................................................... 14 
6.1.2 
Trial Procedures ............................................................................................ 15 
6.2 
Selection of Trial Population ............................................................................ 17 
6.2.1 
Inclusion Criteria .......................................................................................... 17 
6.2.2 
Exclusion Criteria ......................................................................................... 17 
6.3 
Treatments ........................................................................................................ 19 
6.3.1 
Investigational Medicinal Product(s)/ Formulation(s) ................................. 19 
6.3.2 
IMP Dispensation ......................................................................................... 20 
6.3.3 
Instructions for Use and Administration ....................................................... 20 
6.4 
Efficacy and Safety Variables ........................................................................... 21 
6.4.1 
Efficacy Variables ......................................................................................... 21 
6.4.1.1 
Primary Efficacy Endpoints ...................................................................... 21 
6.4.1.2 
Secondary Efficacy Endpoints .................................................................. 21 
6.4.1.3 
Other Pre-specified Efficacy Endpoints .................................................... 21 
6.4.1.4 
Exploratory Efficacy Endpoints ................................................................ 22 
6.4.2 
Safety Variables ............................................................................................ 22 
6.4.3 
Other Endpoints ............................................................................................ 22 
6.5 
Statistical Methods ........................................................................................... 22 


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6.5.1 
Disposition of Subjects ................................................................................. 22 
6.5.1.1 
Completed Subjects .................................................................................. 23 
6.5.1.2 
Discontinued Subjects ............................................................................... 23 
6.5.2 
Protocol Deviations ...................................................................................... 23 
6.5.3 
Data Sets Analyzed ....................................................................................... 23 
6.5.3.1 
Full Analysis Set ....................................................................................... 24 
6.5.3.2 
Per Protocol Set ........................................................................................ 24 
6.5.3.2.1 
Safety Set ............................................................................................... 24 
6.5.4 
Demographic and Other Baseline Characteristics ........................................ 24 
6.5.4.1 
Baseline Ocular Assessments .................................................................... 24 
6.5.4.1.1 
Dryness Score ........................................................................................ 25 
6.5.4.1.2 
Visual Analog Scale (VAS) ................................................................... 25 
6.5.4.1.3 
Ocular Surface Disease Index (OSDI)© ................................................ 25 
6.5.4.1.4 
Best Corrected Visual Acuity (BCVA) .................................................. 25 
6.5.4.1.5 
Slit-Lamp Biomicroscopy ..................................................................... 25 
6.5.4.1.6 
Tear Film Break-Up Time (TFBUT) ..................................................... 25 
6.5.4.1.7 
Corneal Fluorescein Staining ................................................................ 26 
6.5.4.1.8 
Meibomian Gland Assessment (MGD Score) ....................................... 26 
6.5.4.1.9 
Unanesthetized Schirmer’s Test I .......................................................... 26 
6.5.4.2 
Medical and Surgical History ................................................................... 26 
6.5.4.3 
Concomitant Medications and Therapies.................................................. 26 
6.5.4.3.1 
Concomitant Medications...................................................................... 27 
6.5.4.3.2 
Concomitant Therapies .......................................................................... 27 
6.5.5 
Measurements of Subject Dosing Compliance ............................................. 27 
6.5.6 
Extent of Exposure ....................................................................................... 28 
6.5.7 
Analysis of Efficacy ..................................................................................... 29 
6.5.7.1 
Descriptive Statistics ................................................................................. 29 
6.5.7.2 
Unit of Analysis ........................................................................................ 29 
6.5.7.3 
Primary Efficacy Analyses ........................................................................ 29 
6.5.7.4 
Secondary Efficacy ................................................................................... 31 
6.5.7.4.1 
Secondary Efficacy Analyses ................................................................ 31 
6.5.7.4.2 
Other Pre-specified Efficacy Analyses .................................................. 32 
6.5.7.5 
Exploratory Analyses ................................................................................ 32 
6.5.7.6 
Sensitivity Analyses .................................................................................. 33 
6.5.7.6.1 
Sensitivity Analyses for Primary Efficacy Endpoints ........................... 33 
6.5.7.6.2 
Sensitivity Analyses for Secondary Efficacy Endpoints ....................... 33 
6.5.7.6.3 
Sensitivity Analyses for Other Pre-specified Efficacy Endpoints ......... 34 


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6.5.8 
Statistical/Analytical Issues .......................................................................... 34 
6.5.8.1 
Study Days ................................................................................................ 34 
6.5.8.2 
Analysis Visits .......................................................................................... 34 
6.5.8.3 
Study Baseline .......................................................................................... 34 
6.5.8.4 
CDISC Standards ...................................................................................... 34 
6.5.8.5 
Adjustment for Covariates ........................................................................ 35 
6.5.8.6 
Handling of Dropouts or Missing Data ..................................................... 35 
6.5.8.6.1 
Imputation Method for Efficacy Endpoints ........................................... 35 
6.5.8.6.2 
Missing Dates ........................................................................................ 35 
6.5.8.6.3 
Adverse Events ...................................................................................... 36 
6.5.8.7 
Interim Analyses and Data Monitoring ..................................................... 36 
6.5.8.8 
Multicenter Studies ................................................................................... 36 
6.5.8.9 
Multiple Comparisons/Multiplicity .......................................................... 36 
6.5.8.10 
Use of an “Efficacy Subset” of Subjects................................................... 36 
6.5.8.11 
Examination of Subgroups ........................................................................ 36 
6.5.9 
Safety Analyses ............................................................................................ 36 
6.5.9.1 
Adverse Events ......................................................................................... 37 
6.5.9.1.1 
General Considerations for Analysis of Adverse Events....................... 37 
6.5.9.1.2 
Adverse Event Dictionary ..................................................................... 37 
6.5.9.1.3 
Treatment-Emergent Adverse Events .................................................... 37 
6.5.9.1.4 
Adverse Event Severity ......................................................................... 37 
6.5.9.1.5 
Relationship of Adverse Events to Study Drug ..................................... 37 
6.5.9.1.6 
Serious Adverse Events ......................................................................... 37 
6.5.9.1.7 
Summaries of Adverse Event ................................................................ 38 
6.5.9.2 
Safety Laboratory Values .......................................................................... 39 
6.5.9.3 
Vital Sign Measurements .......................................................................... 39 
6.5.9.4 
Other Safety Measurements ...................................................................... 39 
6.5.9.4.1 
Visual Acuity ......................................................................................... 39 
6.5.9.4.2 
Slit-lamp Biomicroscopy ....................................................................... 39 
6.5.9.4.3 
Dilated Fundoscopy Examination ......................................................... 39 
6.5.9.4.4 
Intraocular Pressure ............................................................................... 40 
6.5.10 
Determination of Sample Size ...................................................................... 40 
6.6 
Changes in Planned Analyses ........................................................................... 41 
7 
INDEX OF PLANNED TABLES, FIGURES, AND LISTINGS ........................ 41 
8 
REFERENCES ..................................................................................................... 45 
 


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2.1 
Table of Tables 
Table 1. Schedule of Assessments ........................................................................................... 15 
Table 2. Active Investigational Product ................................................................................... 19 
Table 3. Control/Reference Investigational Product ................................................................ 20 
 
2.2 
Table of Figures 
Figure 1: Trial Design Schematic ............................................................................................ 14 
 
 
 
 


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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Terms or Abbreviations 
Definitions 
AE 
Adverse event 
AICc 
Akaike information criterion with a correction for finite 
sample sizes 
ATC 
Anatomic Therapeutic Chemical 
BCVA 
Best-corrected visual acuity 
BOCF 
Baseline observation carried forward 
cCFS 
Central Corneal Fluorescein Staining 
CFB 
Change from baseline 
CRO 
Clinical Research Organization 
CS 
Clinically significant 
CSR 
Clinical Study Report 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
ET 
Early termination 
ETDRS 
Early Treatment of Diabetic Retinopathy 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigation medicinal product 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
LOCF 
Last observation carried forward 
logMAR 
Logarithm of the minimum angle of resolution 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
Meibomian Gland Dysfunction 


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NCS 
Not clinically significant 
NEI 
National Eye Institute 
OD 
Oculus Dexter (Right eye) 
OS 
Oculus Sinister (Left eye) 
OSDI 
Ocular Surface Disease Index 
OU 
Oculus Uturque (Both eyes) 
PPS 
Per Protocol Set 
PT 
Preferred term 
QID 
4 times daily 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse event 
TFBUT 
Tear Film Break Up Time 
tCFS 
total Corneal Fluorescein Staining 
VA 
Visual acuity 
VAS 
Visual analogue scale 
WHODrug 
World Health Organization Drug Dictionary 


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4 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to frame the analyses and summarization 
of the clinical data from the trial “A Phase 3, Multi-Center, Randomized, Double-Masked, 
Saline-Controlled Trial to Evaluate the Effect of NOV03 (Perfluorohexyloctane) on Signs 
and Symptoms of Dry Eye Disease Associated with Meibomian Gland Dysfunction (Mojave 
Study)”.  
 
The content and structure of this SAP provide sufficient detail to meet the requirements 
identified by the United States Food and Drug Administration (FDA) as outlined in the “E9 
Statistical Principles for Clinical Trials,” revised as of September 1998, and International 
Council for Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials. 
 
The following documents were used in the preparation of this SAP: 
 
• Protocol 904, Amendment 1, 09 November 2020 
 
• Electronic case report forms (eCRFs) for Protocol 904 (dated 22 September 2020) 
 
The following CDISC standards will be used for the analysis and summarization outlined in 
this SAP: 
 
Exchange Standards 
SDTM 1.7 / SDTM IG v3.3 
ADaM 2.1 / ADaM IG v1.2 
Define.xml v2.0 
Terminology Standards 
CDISC SDTM 2020-09-25 
CDISC ADaM 2020-09-25 
MedDRA v22.1 
WHODRUG B3 GLOBAL (SEPT 2019) 
 
The SAP provides details of the protocol-specified analyses of efficacy and safety that will be 
completed in support of the clinical study report (CSR) for Protocol 904. Changes made to 
the SAP after finalization, but before database lock and unmasking, will be documented in an 
amendment and the changes summarized at the beginning of this document. Any deviations 
from these guidelines will be documented in the CSR. Any post hoc or unplanned analyses 
will also be identified as such if they are included in the CSR. 
 
The trial will be multi-center, randomized, double-masked, and saline-controlled for 
evaluating the efficacy, safety, and tolerability of NOV03 (perfluorohexyloctane) ophthalmic 
solution in comparison to a saline control for the treatment of the signs and symptoms of Dry 
Eye Disease (DED) 
. 
 
To demonstrate efficacy (superiority of NOV03 to saline) in two primary endpoints, change 
from baseline (CFB) in total Corneal Fluorescein Staining (tCFS) (National Eye Institute 


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(NEI) scale) at Day 57 and CFB in Dryness Score (visual analogue scale [VAS] Severity of 
Dryness) at Day 57, a hierarchical fixed sequence testing will be employed to maintain type I 
error rate.  
 
Using the Full Analysis Set (FAS), the difference in the mean CFB of tCFS at Day 57 
between treatments will be tested first. If the test of the difference (NOV03 minus saline) is 
statistically significant at the 0.05 significance level and in favor of NOV03 (difference less 
than 0), NOV03 will be declared to be superior to saline in the mean CFB of tCFS, the trial 
will be considered a success, and the difference in the mean CFB of Dryness Score (VAS 
Severity of Dryness) at Day 57 between treatments using FAS will also be tested.  
 
If in addition to a statistically significant test of the difference in the mean CFB of tCFS at 
Day 57 which is in favor of NOV03, the test of the difference in the mean change from 
Dryness Score (VAS Severity of Dryness) at Day 57 is also statistically significant at 0.05 
significant level and in favor of NOV03, then NOV03 will be declared to be superior to 
saline in both the mean CFB of tCFS and the mean CFB of Dryness Score (VAS Severity of 
Dryness) at Day 57. 
 
• Masking - This is a double-masked trial (NCI Preferred Term ‘Double Blind Study’). 
The subjects, investigators, Clinical Research Organization (CRO) personnel involved 
in conduct and monitoring of the trial and sponsor will be masked with respect to the 
investigational medicinal product (IMP) assignment. Due the physicochemical 
differences between NOV03 and saline, there will be a dedicated dosing coordinator 
who will be responsible for the handling of IMP and activities (such as dispensation, 
collection, and accountability) surrounding the use of IMP. This designee shall not 
participate in any other trial procedures and shall not report this information to other 
staff. The investigational drug and control will be provided in identical bottles and 
labels to ensure the double-masked character of the trial. Subjects will be instructed to 
administer the IMP out of the sight of the Investigator or site staff other than the 
dedicated dosing coordinator and are not to discuss IMP characteristics and/or their 
experience with the IMP. 
 
• Treatment assignment method - Subjects who meet all inclusion and exclusion 
criteria at Visits 0 and 1 will be randomized to a treatment group NOV03 (100% 
perfluorohexyloctane) or saline (0.6% sodium chloride solution) in a 1:1 ratio 
stratified by clinical site and dryness score <70 vs ≥ 70 (VAS) at baseline (Visit 1). 
Subjects who fail to qualify for the trial at screening may be rescreened (see Section 
6.2).   
 
An Interactive Response System (IRS) will be used to account for the stratification 
factors while assigning the drug kit numbers at Visits 1, 2 and 3. Each treatment 
group of this trial will consist of approximately 280 subjects, such that approximately 
250 evaluable subjects per arm complete the trial, for an estimated total of 560 
randomized subjects. Specifically, the treatments are defined as follows: 
 


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 Treatment 1: NOV03 (100% perfluorohexyloctane), 4 times daily (QID) 
 Treatment 2: Saline (0.6% sodium chloride solution), QID 
 
• Packaging and labeling -  The IMP will be labelled according to the legal 
requirements and packaged into individual subject kits, each containing 2 bottles of 
NOV03 or saline solution. In compliance with the Code of Federal Regulations 21 
part 312, section 312.6, the labels for the IMP shall be comprised of: 
 
 Protocol number  
 Kit number 
 Investigational new drug statement 
 Storage conditions 
 Name and address of the sponsor 
 
• Trial configuration - This is a parallel trial design (NCI Preferred Term ‘Parallel 
Study’). Subjects will be randomized to either NOV03 QID or saline QID in a 1:1 
ratio. Subjects will self-administer one drop of masked investigation product in the 
lower cul-de-sac of each eye QID at approximately the same time e.g., morning, lunch 
time/midday, afternoon/early evening, and at bedtime. Note: if a dose is missed, the 
next dose should be administered on time. 
• Type of control used - This is a saline-controlled (NCI Preferred Term ‘Placebo 
Control’), superiority trial.  
 
• Duration of the trial - The estimated trial duration is approximately 7 months, from 
first subject first visit to last subject last visit. An individual subject’s participation 
will involve 5 visits over approximately a 10-week period, including screening. After 
the trial, subjects will be treated according to standard of care, at the discretion of the 
treating physician.  
 
• Number of clinical sites and countries involved - Approximately 35 clinical sites in 
the United States will randomize approximately 560 (280 in each treatment group) 
subjects. 
 
• Interim analyses - No interim analyses are planned for this trial. 
 
• Power - A true difference in the mean CFB of tCFS score at Day 57 of -1.0 (NOV03 
minus saline) with a common standard deviation of 2.8, and a true difference in the 
mean CFB of Dryness Score (VAS Severity of Dryness) at Day 57 of -10 (NOV03 
minus saline) with a common standard deviation of 28 were assumed for the sample 
size calculation. To demonstrate superiority of NOV03 over saline in the mean CFB 
of tCFS score at Day 57 with a two-sided alpha of 0.05 and superiority of NOV03 
over saline in the mean CFB of Dryness Score (VAS Severity of Dryness) at Day 57 
with a two-sided alpha of 0.05, a minimum number of 250 FAS subjects (study eyes) 


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per treatment group will be needed to achieve 95.8% power assuming independence 
between tCFS score and Dryness Score (VAS Severity of Dryness).  A positive 
correlation between these two endpoints would increase the overall power.  
 
Accounting for an assumed 10% subject discontinuation rate, approximately 560 
subjects (280 subjects each arm) will be randomly assigned to trial treatment such that 
approximately 250 evaluable participants per arm complete the trial. 
 
5 
TRIAL OBJECTIVES 
5.1 
Primary Objective  
The primary objective of this trial is to assess the efficacy of NOV03 (perfluorohexyloctane) 
ophthalmic solution at a QID dosing regimen in comparison to a saline control for the 
treatment of the signs and symptoms of DED 
. 
The population-level summaries of the primary estimands are: 
 
• Difference in mean CFB of tCFS score (NEI scale) at Day 57 (NOV03 minus saline) 
• Difference in mean CFB of Dryness Score (VAS Severity of Dryness) at Day 57 
(NOV03 minus saline) 
5.2 
Secondary Objectives 
The secondary objective of this trial is to assess the safety and tolerability of NOV03 
(perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in comparison to a 
saline control in subjects with DED 
. This will be evaluated by 
monitoring ocular and non-ocular adverse events (AE), visual acuity, slit-lamp 
biomicroscopy, intraocular pressure, dilated fundoscopy, instillation comfort questionnaire, 
and eyedrop acceptability questionnaire.  
Further objectives of this trial are to explore the effect on other efficacy endpoints of NOV03 
(perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in comparison to a 
saline control in subjects with DED 
. This will be evaluated by: 
• CFB of Dryness Score (VAS) at Day 15 
• CFB in tCFS (NEI scale) at Day 15 
• CFB of VAS burning/stinging at Day 29 
• CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
• CFB of Dryness Score (VAS) at Day 29 
• CFB in CFS central and inferior sub-regions (NEI scale) to each measured post-
baseline visit 
• Proportion of tCFS responders (≥3 improvement based on NEI scale) at Day 57 
• Proportion of Dryness Score responders (≥30% improvement from baseline) at Day 
57 




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6.1.1 
Trial Design Diagram 
Figure 1: Trial Design Schematic 
 
 
 






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Page 17 of 45 – CONFIDENTIAL 
6.2 
Selection of Trial Population 
All subjects must be at least 18 years of age, of either gender and any race. Subjects must 
have a reported history of dry eye in both eyes and meet all inclusion criteria and none of the 
exclusion criteria.  
If the subject does not qualify at Visit 0 or Visit 1, he or she may be re-screened once after 14 
days from the relevant visit provided that new informed consent to be signed, new subject 
number received via IRS and all the assessments are repeated as per protocol requirements. 
Key inclusion and exclusion criteria are detailed below. Full details can be found in the 
protocol. 
6.2.1 
Inclusion Criteria 
Subjects will be eligible to participate in this trial if they meet all following criteria:  
1. Be at least 18 years of age at the time of consent. 
2. Provide written informed consent. 
3. Have a subject reported history of Dry Eye Disease in both eyes for at least 6 months prior 
to Visit 0. 
4. Have Tear film break-up time (TFBUT) ≤5 sec at Visit 0 and Visit 1. 
5. Have Ocular Surface Disease Index (OSDI) ≥25 at Visit 0 and Visit 1. 
6. Have an unanesthetized Schirmer’s Test I ≥5 mm at Visit 0 and Visit 1. 
7. 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 0 and Visit 1. 
8. Have a total corneal fluorescein staining score of 4≤ X ≤11 (i.e. sum of inferior, superior, 
central, nasal, and temporal) according to the National Eye Institute (NEI) scale at Visit 0 
and Visit 1.   
9. Have at least one eye (the same eye) satisfy all criteria for 4, 6, 7, and 8 above at Visit 0 
and Visit 1. 
10. Be able and willing to follow instructions, including participation in all trial assessments 
and visits. 
6.2.2 
Exclusion Criteria 
Subjects will not be eligible to participate in this trial if any of the following criteria apply: 
1. Have been randomized in NVU-002, NVU-003 or participated in the NVU-004 OLE 
Study. 
2. Have any clinically significant ocular surface slit-lamp findings at Visit 0 and Visit 1 and/or 
in the opinion of the investigator have any findings that may interfere with trial parameters 
and may include eye trauma, history of eye trauma or anterior membrane dystrophy. 
3. Have a history of Stevens Johnson Syndrome. 
4. Have active blepharitis or lid margin inflammation that required any topical antibiotics or 
topical steroids within last 30 days prior to Visit 0 or will require such treatment during the 


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trial. Any other lid margin therapy such as lid scrubs, lid wipes, warm compresses, systemic 
antibiotics (such as tetracyclines) and oral supplements for treatment of ocular conditions 
or oral supplements had to be stable within the last 30 days prior to Visit 1 and should be 
maintained stable throughout the trial.  
5. Have had a LipiFlow procedure, Intense Pulse Light (IPL) procedure or any kind of other 
procedures affecting meibomian glands within 6 months prior to Visit 1. 
6. Have abnormal lid anatomy that causes incomplete eyelid closure including entropion and 
ectropion or floppy lid syndrome that exposes parts of the conjunctiva or impairs the 
blinking function of the eye. 
7. Have received or removed a permanent punctum plug within 3 months (6 months for 
dissolvable punctum plugs) prior to Visit 1 or expected to receive a punctum plug or 
removal of a punctum plug, or a punctum plug expected to be dissolved during the trial.  
8. Have Dry Eye Disease secondary to scarring, irradiation, alkali burns, cicatricial 
pemphigoid, or destruction of conjunctival goblet cells (as with vitamin A deficiency). 
9. Have an ocular or periocular malignancy. 
10. Have a corneal epithelial defect; have significant confluent staining or filaments anywhere 
on the cornea.  
11. Have a history of herpetic keratitis. 
12. Have active ocular allergies or ocular allergies that are expected to be active during the 
trial period. 
13. Be diagnosed with an active ocular or systemic infection (bacterial, viral, or fungal), 
including fever requiring treatment with antibiotics. 
14. Have worn contact lenses within 1 month of Visit 0 or anticipate using contact lenses 
during the trial. 
15. Have used any eye drops and/or TrueTearTM device (Intranasal Tear Neurostimulator) 
within 24 hours before Visit 1. 
16. Have had intra-ocular surgery or ocular laser surgery within the previous 6 months or have 
any planned ocular and/or lid surgeries over the trial period. 
17. Be a family member living in the same household of another randomized study 904 or 
NVU-003 subject, or a family member living in the same household of another NVU-004 
OLE participant. 
18. Be a clinical site employee that is directly involved in the management, administration, or 
support of this trial or be an immediate family member of the same.  
19. Be a woman who is pregnant, nursing or planning a pregnancy. 
20. Be unwilling to submit to a urine pregnancy test at Visit 0, Visit 1 and Visit 4 (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 bilateral tubal 
ligation or bilateral oophorectomy) or is post-menopausal (without menses for 12 
consecutive months). 
21. 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 (IUD); or surgical sterilization 
of partner. For non-sexually active females, abstinence may be regarded as an adequate 






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the duration of the trial. Clinic staff will coach the subjects to dose themselves at 
approximately the same time every day e.g., morning, lunch time/mid-day, afternoon/early 
evening, and at bedtime. If a dose is missed, then the next dose should be administered on 
time. 
Dosing should be continued until the morning of the next Visit (should be at least 2 hours 
before first ophthalmic examination).  
The bottles are designed for multiple use. Subjects will be instructed to only open one bottle 
at a time. They should be instructed not to discard the empty bottles but keep them in the kit 
box and return them at their next visit in the kit box. Subjects will record in their dosing diary 
that their doses were taken. Subjects will be instructed not to show the assigned IMP to the 
Investigator or site staff other than the dedicated dosing coordinator, unless instructed to do 
so. 
6.4 
Efficacy and Safety Variables 
6.4.1 
Efficacy Variables 
6.4.1.1 
Primary Efficacy Endpoints 
Two primary endpoints will be tested in the following order using hierarchical fixed sequence 
testing: 
 
1. Change from baseline (CFB) in tCFS (NEI scale) at Day 57 
2. CFB of Dryness Score (VAS Severity of Dryness) at Day 57 
 
6.4.1.2 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be evaluated in the following order using 
hierarchical fixed sequence testing: 
 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in tCFS (NEI scale) at Day 15 
3. CFB of VAS burning/stinging at Day 57 
4. CFB in cCFS (NEI scale) at Day 57 
 
6.4.1.3 
Other Pre-specified Efficacy Endpoints 
1. CFB of Dryness Score (VAS) at Day 29 
2. CFB in tCFS at Day 29 
3. CFB in CFS central and inferior sub-regions (NEI scale) to each measured post-
baseline visit 
4. Proportion of tCFS responders (≥3 improvement based on NEI scale) at Day 57 
5. Proportion of Dryness Score responders (≥30% improvement from baseline) at Day 
57 




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6.5.1.1 
Completed Subjects 
A completed subject is one who is not a screen failure and has not been discontinued from the 
trial. 
6.5.1.2 
Discontinued Subjects  
Notification of a subject discontinuation and the reason for study discontinuation will be 
made to the CRO and/or trial sponsor and will be clearly documented in the eCRF as: 
• Adverse event 
• Lack of efficacy  
• Withdrawal by subject 
• Protocol violation 
• Lost to follow-up 
• Death 
• Other 
 
Subjects who discontinue for any reason after randomization will not be replaced. 
6.5.2 
Protocol Deviations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the sponsor and the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and agreed to by the investigator. Deviations will 
be collected in the CRF. Deviations usually have an impact on individual subjects or a small 
group of subjects and do not involve inclusion/exclusion or primary endpoint criteria. 
 
Major protocol deviations that could potentially affect the efficacy and result in removal from 
the PPS will be assessed and identified prior to database lock and unmasking. Major protocol 
deviations will be summarized by treatment and overall. 
 
6.5.3 
Data Sets Analyzed 
Inclusion into the Full Analysis Set (FAS) and Safety Set (SAF) will be determined 
programmatically from the study data collected. Inclusion in the PPS will be determined 
programmatically from the eCRF data and a blinded Sponsor review.  
 
The statistical analysis of safety data will be performed for the SAF. The analysis of baseline 
and efficacy data will be performed for the FAS. The primary efficacy analyses will also be 
performed on the PPS as sensitivity analyses. 
 
A tabulation of the three analysis sets will presented by treatment and overall. 


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6.5.3.1 
Full Analysis Set 
The FAS includes all randomized subjects who received at least one dose of investigational 
product. The primary analysis will be performed on the FAS. Subjects in the FAS will be 
analyzed as randomized. 
6.5.3.2 
Per Protocol Set 
The PPS includes subjects in the FAS who do not have significant protocol deviations and 
who complete the study. Protocol deviations will be assessed prior to database lock and 
unmasking. The PPS will be analyzed using observed data only for efficacy variables. 
Subjects in the PPS will be analyzed as treated. 
6.5.3.2.1 
Safety Set  
The SAF includes all randomized subjects who have received at least one dose of the 
investigational product. The SAF will be analyzed for all safety assessments. Subjects in the 
SAF will be analyzed as treated. 
6.5.4 
Demographic and Other Baseline Characteristics 
Quantitative variables will be summarized using number of subjects (n), mean, median, 
standard deviation, minimum and maximum. The mean, median, and standard deviation will 
be presented with one more decimal place than the collected data and the minimum and 
maximum will be presented with the same decimal places as the collected data. The 
qualitative variables will be summarized using counts and percentages. All summaries will be 
presented by treatment group and overall in FAS, PPS, and SAF.  
 
The following demographic and baseline characteristics will be summarized by treatment 
group and overall:  
• Age (years) 
• Age category (years) - <18, ≥18 to <65, ≥65 
• Sex 
• Race 
• Ethnicity 
• Iris color 
• Eyes qualified for the study – right eye (OD), left eye (OS), both eyes (OU) 
• Study Eye – OD, OS 
 
Age will be calculated as (randomization date – date of birth) /365.25. 
6.5.4.1 
Baseline Ocular Assessments  
Baseline ocular assessments will be summarized by treatment and overall for the FAS, PPS, 
and SAF. 


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6.5.4.1.1 
Dryness Score  
Baseline dryness score will be summarized using descriptive statistics by treatment group and 
overall. Assessment for both eyes is done simultaneously.  
6.5.4.1.2 
Visual Analog Scale (VAS) 
Dry eye symptoms (sticky feeling, burning/stinging, foreign body sensation, itching, blurred 
vision, sensitivity to light, and pain), awareness of dry eye symptoms and frequency of 
dryness will be summarized using descriptive statistics by treatment group and overall. 
Assessment for both eyes is done simultaneously.  
6.5.4.1.3 
Ocular Surface Disease Index (OSDI)© 
Baseline OSDI score will be summarized using descriptive statistics by treatment group and 
overall. Assessment for both eyes is done simultaneously. The OSDI questionnaire consists of 
12 questions, with possible answers of ‘All of the time’, ‘Most of the time’, ‘Half of the 
time’, ‘Some of the time’ and ‘None of the time’. To score the questionnaire, ‘All of the time’ 
is given a numerical value of 4, ‘Most of the time’ a value of 3, ‘Half of the time’ a value of 
2, ‘Some of the time’ a value of 1, and ‘None of the time’ a value of 0. The OSDI score is 
calculated as:  
OSDI=
(sum of scores) × 25
(# of questions answered) 
6.5.4.1.4 
Best Corrected Visual Acuity (BCVA) 
LogMAR Visual Acuity (VA) will be assessed in the right eye (OD). The procedure will be 
repeated for the left eye (OS). Subjects should use the most recent correction to attain their 
best-corrected visual acuity (BCVA). BCVA will be evaluated using the calculated logMAR 
score. Baseline BCVA of the study eye will be summarized using descriptive statistics by 
treatment group and overall.  
6.5.4.1.5 
Slit-Lamp Biomicroscopy 
Lids, cornea, conjunctiva, anterior chamber, iris and lens for OD and OS will be examined. 
Observations will be graded as Normal, Abnormal CS (clinically significant) and Abnormal 
NCS (not clinically significant). Baseline slit-lamp biomicroscopy results of the study eye 
will be summarized using descriptive statistics by treatment group and overall.   
6.5.4.1.6 
Tear Film Break-Up Time (TFBUT) 
For each eye, two measurements will be taken and TFBUT will be the average unless the two 
measurements are >2 seconds apart and are each <10 seconds, in which case, a third 
measurement would be taken and TFBUT will be the average of the two closest of the three. 
In all cases, only two values will be entered into the case report form. Baseline TFBUT of the 
study eye will be summarized using descriptive statistics by treatment group and overall. 


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6.5.4.1.7 
Corneal Fluorescein Staining 
Corneal fluorescein staining will be graded with the NEI Grading Scale. A standardized 
grading system of 0-3 is used for each of the five areas on each cornea. Grade 0 will be 
specified when no staining is present. The maximum total score for each eye is 15. Baseline 
corneal fluorescein staining of the study eye will be summarized using descriptive statistics 
by treatment group and overall.   
6.5.4.1.8 
Meibomian Gland Assessment (MGD Score) 
The secretion of 5 central glands on the lower eyelid will be evaluated for each eye. Each of 
the 5 glands will be scored from 0-3: 0 = normal, 1 = thick/yellow, whitish, particulate; 2 = 
paste; 3 = none/occluded. The total score will thus range from 0-15. Baseline MGD score of 
the study eye will be summarized using descriptive statistics by treatment group and overall.   
6.5.4.1.9 
Unanesthetized Schirmer’s Test I 
Schirmer’s Tear Test I will be performed ≥5 minutes after MGD evaluation. The length of the 
moistened area of the Schirmer test strip will be recorded (mm) for each eye. Baseline 
unanesthetized Schirmer’s Test I of the study eye will be summarized using descriptive 
statistics by treatment group and overall.   
6.5.4.2 
Medical and Surgical History 
Medical history, including ocular medical history, will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA version 22.1 or higher). Non-ocular medical 
history will be summarized by system organ class (SOC) and preferred term (PT) by 
treatment group and overall in the FAS. SOC will be sorted alphabetically. PT will be sorted 
by descending frequency overall within each SOC. Subjects with a particular medical history 
event or medical history class will be counted once at the PT level and once at the SOC level. 
Ocular medical history will be summarized at the subject and eye levels by treatment group 
and overall in the FAS with separate summaries for the study eye and fellow eye. 
 
Surgical history will not be coded in this trial and thus all data as collected in the CRF will be 
provided in data listings. Data listings will be provided for medical history as well. 
 
6.5.4.3 
Concomitant Medications and Therapies 
Concomitant medications will be coded to the Anatomical Therapeutic Chemical (ATC) 
classification levels 1-4 and preferred terms using the World Health Organization Drug 
Dictionary (WHODrug B3 Global Sept 2019). 
 
Non-ophthalmic concomitant medications will be summarized by ATC Level 3 (therapeutic 
subgroup) and preferred term by treatment group and overall in the FAS. ATC Level 3 terms 
will be sorted alphabetically. Preferred terms will be sorted by descending frequency overall 
within ATC Level 3 term. Subjects receiving a particular medication or medication of ATC 
Level 3 will be counted once at the preferred term level and once at ATC Level 3.  


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Ophthalmic concomitant medications will be summarized at the eye level, separately for 
study and fellow eyes, and at the subject level by ATC Level 3 and preferred term by 
treatment group and overall in the FAS. 
 
Concomitant therapies will not be coded in this trial and thus all data as collected in the CRF 
will be provided in data listings. Data listings will be provided for concomitant medications 
as well. 
 
6.5.4.3.1 
Concomitant Medications 
A medication is considered concomitant if the start date is on or after the date of first dose of 
study drug or if the start date is prior to the first dose of study drug but the end date is after 
the date of first dose of the study drug. Partial dates will be imputed using the imputation rule 
specified in section 6.5.8.6.2. If the medication was started prior to first dose of study drug 
and the stop date is unknown or ongoing, the medication will be considered concomitant. If 
the start date or stop date is completely missing and it is unclear as to whether the medication 
is concomitant, the medication will be conservatively assumed as a concomitant medication. 
6.5.4.3.2 
Concomitant Therapies 
A therapy is considered concomitant if the start date is on or after the date of first dose of 
study drug or if the start date is prior to the first dose of study drug but the end date is after 
the date of first dose of the study drug. Partial dates will be imputed using the imputation rule 
specified in section 6.5.8.6.2. If the therapy was started prior to first dose of study drug and 
the stop date is unknown or ongoing, the therapy will be considered concomitant. If the start 
date or stop date is completely and it is unclear as to whether the therapy is concomitant, the 
therapy will be conservatively assumed as a concomitant therapy.  
6.5.5 
Measurements of Subject Dosing Compliance 
The overall subject dosing compliance will be assessed using the data from the daily dosing 
diary eCRFs and will be summarized by treatment group in the SAF.   
Subject dosing compliance is defined as the proportion of the number of doses administered 
out of the number of doses that should have been administered per protocol. On the first day 
of dosing, the expected number of doses will be based on the time of initial dose (24-hour 
clock) on the ‘Dispense Investigational Product’ form. If the initial dose in clinical occurs 
prior to 10:00, then four total doses should be administered that day (morning, lunch 
time/mid-day, afternoon/early evening, and at bedtime). If the initial dose in clinic occurs 
between 10:00 and 13:59, then three total doses should be administered that day (lunch 
time/mid-day, afternoon/early evening, and bedtime). If the initial dose occurs on or after 
14:00, then two total doses should be administered that day (afternoon/early evening and 
bedtime). On the last day of dosing, if the time of last dose (24-hour clock) on the ‘Visit Date’ 
form is before 12:00, then only one dose should be administered that day. If the time of last 
dose (24-hour clock)  is on or after 12:00 and before 14:00 then two total doses should be 
administered that day. If the time of last dose is on or after 14:00 then three total doses should 


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be administered that day. If the last dose is not on the day of the visit, then the time of 
Dryness Score evaluation will be used to determine the expected number of doses. If the time 
of Dryness Score is after 12:00 and before 14:00, then only one dose should be administered 
that day. If the time of Dryness Score is on or after 14:00 and before 16:00, then two total 
doses should be administered. If the time of Dryness Score is on or after 16:00, then three 
total doses should be administered. The dosing compliance (%) will be calculated as (total 
number of doses administered/ total number of doses that should have been 
administered)*100.   
  
In the event that the dosing diary is not returned, the total number of doses that should have 
been administered will be adjusted. The days with the dosing diary not returned will be 
excluded from the denominator. For example, if at Visit 2, 2 days are not returned, exclude 
those 2 days from the denominator and the number of doses that should have been 
administered will be adjusted from 56 to 48. 
 
Compliance will be summarized using descriptive statistics in each treatment group and 
overall in the SAF. Compliance will be presented categorically by treatment group and 
overall: 
 
• < 50% 
• 50-<80% 
• 80-<90% 
• 90-100% 
• >100%-120% 
• >120% 
 
6.5.6 
Extent of Exposure  
Exposure to study drug will be summarized in days. Exposure will be calculated as (last dose 
date – first dose date + 1). Duration of exposure will be summarized using descriptive 
statistics in each treatment group and overall in the SAF. Duration of exposure will be 
presented categorically: 
• < 15 days 
• 15-<29 days 
• 29-<57 days 
• ≥57 days 
 
Dosing information for each treatment and each subject will be listed. Discontinuation of 
treatment will be summarized by treatment received. The primary reason for IMP 
discontinuation will also be summarized by treatment received. 


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6.5.7 
Analysis of Efficacy 
6.5.7.1 
Descriptive Statistics 
Quantitative variables will be summarized using number of subjects (n), mean, median, 
standard deviation, minimum and maximum. The mean, median, and standard deviation will 
be presented with one more decimal place than the collected data and the minimum and 
maximum will be presented with the same decimal places as the collected data. The 
qualitative variables will be summarized using counts and percentages. Summaries will be 
presented by treatment group in the FAS and PPS.  
All primary and secondary analyses will be two-sided at a significance level of 0.05. 
6.5.7.2 
Unit of Analysis 
For efficacy endpoints, the unit of analysis will be the study eye as defined by the following: 
Eyes are eligible for analysis if they meet all of the inclusion criteria. In the case that both 
eyes are eligible for analysis, the worst eye shall be chosen, and this will be defined as the 
eye with worse (higher) total corneal staining at Visit 1. If the total corneal staining is the 
same in both eyes then the right eye will be selected as the study eye. 
6.5.7.3 
Primary Efficacy Analyses 
The primary comparisons in this trial will be between NOV03 versus saline at Day 57 in the 
FAS with available data per subject using the following estimands 
 
• Endpoint: 
 CFB in tCFS in the study eye at Day 57 
 CFB of Dryness Score (VAS) at Day 57 
 
• Intercurrent event:  
 Discontinuation of study medications is ignored. [treatment policy strategy] 
 Non-optimal compliance is ignored. [treatment policy strategy] 
 Withdrawal due to any reason. Missing data not imputed. [hypothetical 
strategy if overall study discontinuation rate is <5%] 
 
• Population-level summary: 
 Difference in the mean CFB in tCFS in the study eye at Day 57 between 
NOV03 and saline 
 Difference in the mean CFB of Dryness Score (VAS) at Day 57 between 
NOV03 and saline  
 
If the overall study discontinuation rate in the FAS is ≥5% then the primary analysis will be 
based on imputation methodology using the following estimands: 
 
• Endpoint: 


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 CFB in tCFS in the study eye at Day 57 
 CFB of Dryness Score (VAS scale) at Day 57 
 
• Intercurrent event:  
 Discontinuation of study medications is ignored. [treatment policy strategy] 
 Non-optimal compliance is ignored. [treatment policy strategy] 
 Withdrawal due to lack of efficacy or adverse events: baseline observation 
carried forward (BOCF) is used to impute missing data [hypothetical strategy 
if overall study discontinuation rate ≥5%] 
 Missing data without withdrawal or withdrawal due to reasons other than lack 
of efficacy or adverse events: multiple imputations using randomized 
treatment-based Markov Chain Monte Carlo (MCMC) is used to impute 
missing data [hypothetical strategy if overall study discontinuation rate ≥5%] 
 
• Population-level summary: 
 Difference in the mean CFB in tCFS in the study eye at Day 57 between 
NOV03 and saline 
 Difference in the mean CFB of Dryness Score (VAS scale) at Day 57 between 
NOV03 and saline  
 
The primary comparison in this trial will be between NOV03 versus saline at Day 57. The 
primary efficacy endpoints (e.g. CFB in total corneal fluorescein staining [NEI scale] and 
Dryness Score) will be tested using hierarchical fixed sequence testing and summarized 
descriptively (n, mean, standard deviation, median, min, and max) and analyzed separately 
using an ANCOVA model with terms for baseline value, and treatment. 
Least squares mean for each treatment group and for the difference between treatment groups 
will be presented from each model together with two-sided p-values (used for primary 
inference) and 95% confidence intervals. 
Sample SAS ANCOVA code: 
PROC GLM DATA=INDATA; 
  CLASS <TREATMENT>; 
  MODEL <ENDPOINT>=<TREATMENT> <BASELINE>; 
  LSMEANS <TREATMENT> / CL ALPHA=0.05; 
  LSMEANS <TREATMENT> / PDIFF CL ALPHA=0.05; 
RUN; 
 
Additional robustness analyses will include repeating the primary analysis on the PPS; the  
FAS imputing missing data using last observation carried forward (LOCF); the FAS imputing 
missing data using MCMC multiple imputation methodology under different assumptions of 
missingness (at random and not at random) each using 30 imputed values. 
 
Sample SAS MCMC MI (missing at random): 
PROC MI DATA=INDATA SEED=97656 OUT=OUTDATA MINIMUM=0 MAXIMUM=3 ROUND=1 
NIMPUTE=30; 
  MCMC INITIAL=EM; 


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  BY <TREATMENT>; 
  VAR <BASELINE> <PARAMETER>; 
RUN; 
Where <PARAMETER> has 5 levels and refers to the CFS for each region (inferior, superior, 
central, temporal, and nasal). 
 
Sample SAS MCMC MI (not missing at random): 
PROC MI DATA=INDATA SEED=36797 OUT=MDATA MINIMUM=0 MAXIMUM=3 ROUND=1 
NIMPUTE=30; 
  MCMC IMPUTE=MONOTONE; 
  VAR <BASELINE> <PARAMETER>; 
RUN; 
 
PROC MI DATA=MDATA SEED=38549 OUT=OUTDATA2 MINIMUM=. 0 0 MAXIMUM=. 3 3 
ROUND=. 1 1; 
  CLASS <TREATMENT>; 
  MONOTONE REG(<PARAMETER>=<BASELINE> / DETAILS); 
  MNAR MODEL(<PARAMETER> / MODELOBS=(<TREATMENT>=’Saline’)); 
  VAR <TREATMENT> <BASELINE> <PARAMETER>; 
RUN; 
 
Where <PARAMETER> has 5 levels and refers to the CFS for each region (inferior, superior, 
central, temporal, and nasal). 
 
6.5.7.4 
Secondary Efficacy 
6.5.7.4.1 
Secondary Efficacy Analyses 
The following secondary endpoints will be tested hierarchically: 
 
1. CFB in Dryness Score (VAS scale) at Day 15 
2. CFB in tCFS (NEI scale) at Day 15 
3. CFB in VAS burning/stinging at Day 57 
4. CFB in cCFS (NEI scale) at Day 57 
 
Inference will only be made on these endpoints, at a 2-sided alpha = 0.05, if both primary 
endpoints and any higher order secondary endpoints are statistically significant at a 2-sided 
alpha = 0.05 in favor of NOV03. 
Quantitative secondary efficacy endpoints will be summarized similarly to the primary 
efficacy endpoints. 
The primary analysis of the secondary endpoints will use the FAS with available data per 
subject, assuming the overall study discontinuation rate is <5%. If the overall study 
discontinuation rate is ≥5%, then the primary analysis of the secondary endpoints will be 
based on imputation methodology as defined in Section 6.5.7.3 and the available data 
analyses will become robustness analyses. 




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6.5.7.6 
Sensitivity Analyses 
6.5.7.6.1 
Sensitivity Analyses for Primary Efficacy Endpoints 
Two-sample t-tests (equal variance assumed), Wilcoxon rank sum tests and mixed-effect 
repeated measures analysis comparing treatment groups will be performed as sensitivity 
analyses. The mixed-effect repeated measures model will include treatment, baseline value, 
visit, and the interaction between treatment and visit as fixed effects, and subject as a random 
effect. An unstructured covariance matrix will initially be used to model the covariance 
among repeated measures; however, if the model fails to converge using this covariance 
structure, either heterogeneous TOEPLITZ, homogeneous TOEPLITZ, or compound 
symmetry will be implemented according to the Akaike information criterion with a 
correction for finite sample sizes (AICc). 
Sample SAS two-sample t-test code: 
PROC TTEST DATA=INDATA; 
  CLASS <TREATMENT>; 
  VAR <ENDPOINT>; 
RUN; 
 
Sample SAS Wilcoxon rank sum test code: 
PROC NPAR1WAY DATA=INDATA WILCOXON; 
  CLASS <TREATMENT>; 
  VAR <ENDPOINT>; 
RUN; 
 
Sample SAS mixed-effect repeated measures analysis code: 
PROC MIXED DATA=INDATA; 
  CLASS <TREATMENT> <VISIT> <SUBJECT>; 
  MODEL <ENDPOINT>=<TREATMENT> <VISIT> <TREATMENT>*<VISIT> <BASELINE>; 
  REPEATED <VISIT> / SUBJECT=<SUBJECT> TYPE=UN; 
  RANDOM <SUBJECT>; 
  ESTIMATE ‘NOV03-SALINE’ <TREATMENT> -1 1 / ALPHA=0.05 CL;  
RUN; 
 
Where ‘Saline’ is <TREATMENT>=0 and ‘NOV03’ is <TREATMENT>=1. 
 
6.5.7.6.2 
Sensitivity Analyses for Secondary Efficacy Endpoints 
For quantitative secondary efficacy endpoints, two-sample t-tests, Wilcoxon rank sum tests 
and mixed-effect repeated measures analysis comparing treatment groups will be performed 
as sensitivity analyses.  
The mixed-effect repeated measures model will include treatment, baseline value, visit, and 
the interaction between treatment and visit as fixed effects, and subject as a random effect. 
An unstructured covariance matrix will initially be used to model the covariance among 
repeated measures; however, if the model fails to converge using this covariance structure, 
either heterogeneous TOEPLITZ, homogeneous TOEPLITZ, or compound symmetry will be 
implemented according to the AICc. 


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6.5.7.6.3 
Sensitivity Analyses for Other Pre-specified Efficacy 
Endpoints 
For quantitative efficacy variables, two-sample t-tests, Wilcoxon rank sum tests and mixed-
effect repeated measures analysis will be presented as sensitivity analyses.  
For qualitative efficacy variables, Pearson chi-squared analysis comparing the treatment 
groups will be performed as sensitivity analyses. 
Sample Pearson chi-squared analysis code: 
PROC FREQ DATA=INDATA; 
  TABLES <TREATMENT>*<ENDPOINT> / CHISQ; 
RUN; 
 
6.5.8 
Statistical/Analytical Issues 
6.5.8.1 
Study Days 
Study Day 1 will be defined as the date of Visit 1/Day 1. For events before the Day 1 visit, 
the study day will be calculated as the difference in day between the Day 1 visit and the date 
of interest. Thus, the day prior to the Day 1 visit will be defined as Day -1. 
6.5.8.2 
Analysis Visits 
The eCRF nominal study visits will be used for analysis. For subjects who withdraw from the 
study, if they withdraw at a regular scheduled visit, the data collected at the time of 
withdrawal will be summarized under the regular visit; if they withdraw between scheduled 
visits, the early termination visit will be treated as an unscheduled visit. For the purposes of 
table summarization, the first visit for each nominal study visit will be used. 
6.5.8.3 
Study Baseline  
Baseline measures are defined as the last non-missing measure prior to the initiation of 
randomized study treatment as documented in the subject dosing diary. Per the schedule of 
assessments in the protocol, this is expected to be the Visit 1 value.  Measurements that are 
obtained after the first dose of randomized study treatment will be considered post-baseline 
values.  If a measurement of a variable is not made on a given subject prior to the first dose of 
randomized study treatment, then that subject will be considered not to have a baseline value 
for that variable.  CFB is defined as post-baseline assessment minus baseline assessment.    
6.5.8.4 
CDISC Standards 
The exchange and terminology standards outlined in Section 4 will be used to create SDTM 
domains and ADaM datasets. A reviewer’s guide and define.xml will be produced for each 
set. The ADaM datasets will be used to support all tables, listings, and figures with the 
exception of the pregnancy results listing which will be generated from SDTM. All data in 
the ADaM datasets will be used as the population for listings. At least one listing will be 
created for each ADaM dataset to display (a) most collected variables, and (b) 
derived variables used in the tables and figures. The source listing(s) will be referenced in all 


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table and figure footnotes. 
6.5.8.5 
Adjustment for Covariates 
The primary endpoints are CFB in total corneal fluorescein staining (NEI scale) at Day 57 
and CFB of  Dryness Score (VAS) at Day 57. The two primary endpoints will be analyzed 
separately using an ANCOVA model with baseline measurement as a numeric covariate and 
treatment as the main effect.  
 
Subject randomization is stratified by clinical site and dryness score <70 vs ≥ 70 (VAS) at 
baseline (Visit 1). The analyses will not be adjusted for the stratification factors.   
6.5.8.6 
Handling of Dropouts or Missing Data 
Missing data will be handled as follows. Missing data for other data points not covered below 
will be left as missing. Nominal visits for subjects who withdraw will be handled per Section 
6.5.8.2. 
6.5.8.6.1 
Imputation Method for Efficacy Endpoints 
The primary analysis will be completed on the FAS with available data per subject, assuming 
the overall study discontinuation rate is <5%. If the overall study discontinuation rate is ≥5% 
then the primary analysis will be based on the primary imputation methodology as defined 
Section 6.5.7.3 and the available data analyses will become robustness analyses. 
Additionally, robustness analyses will include repeating the primary analysis on the per 
protocol set (PPS); the FAS imputing missing data using last observation carried forward 
(LOCF); the FAS imputing missing data using Markov Chain Monte Carlo (MCMC) multiple 
imputation methodology under different assumptions of missingness (at random and not at 
random) each using 30 imputed values. 
6.5.8.6.2 
Missing Dates 
All missing dates for medications or events that occur after randomization will be queried for 
a date. If no date is obtained, the following imputation rules will apply: 
 
• For start dates, missing months and days will be imputed as “01”, provided this 
occurs on or after the date of first study drug self-administration. Otherwise, the date 
or month (as appropriate) of the first self-administration of study drug will be used 
• For stop dates, missing months will be imputed as “12” and missing days will be 
imputed as the last day of the month. If this creates a date after 
discontinuation/completion, the date of discontinuation/completion will be used 
The imputed dates will only be used to classify events, medications, or therapy as 
treatment emergent or concomitant. Imputed dates will only be used in the table analyses. 
Listings will display the available date data. 


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6.5.8.6.3 
Adverse Events 
Whether the adverse event occurred after the first dose of study drug, relationship, and 
severity should not be missing and will be queried for value. If missing data is present, the 
AE date will be imputed as detailed above, will be assumed to be related to study drug, and 
will be assumed to be severe. 
6.5.8.7 
Interim Analyses and Data Monitoring 
No interim analyses are planned for this trial. 
6.5.8.8 
Multicenter Studies 
No formal by site analyses will be conducted. Analyses by sites for sites with a sufficient 
number of subjects can be conducted in an adhoc manner to confirm the uniformity of the 
overall results. 
6.5.8.9 
Multiple Comparisons/Multiplicity 
To control for inflation of type 1 error rate due to multiple hypotheses, the analysis of the two 
primary endpoints will be conducted in a hierarchical manner. 
If both primary endpoints demonstrate statistically significant superiority of NOV03 versus 
saline at the two-sided alpha = 0.05 level, the following secondary endpoints will be tested 
hierarchically to maintain an overall two-sided alpha = 0.05. 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central cCFS (NEI scale) at Day 57 
 
6.5.8.10 
Use of an “Efficacy Subset” of Subjects 
The primary analysis will be repeated in the PPS with observed data only as sensitivity 
analysis. Subjects in the PPS will be analyzed as treated.  
6.5.8.11 
Examination of Subgroups 
If imbalances of interest are noted in the demographics and baseline characteristics, ad hoc 
summaries by subgroup can be produced. 
6.5.9 
Safety Analyses 
All safety analyses will be performed on the SAF. The primary evaluation of safety of the 
active arm will be against the control arm. 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 37 of 45 – CONFIDENTIAL 
6.5.9.1 
Adverse Events 
6.5.9.1.1 
General Considerations for Analysis of Adverse Events 
General considerations for AE summaries and calculations are: 
• Multiple events by PT and SOC will be counted once per subject for each treatment 
• For summaries by severity, the most severe event will be selected 
• For summaries by relationship, the most related event will be selected 
6.5.9.1.2 
Adverse Event Dictionary 
AEs will be coded using MedDRA version 22.1 or higher. Tables and listings will present 
data at the system organ class and preferred term level.  
6.5.9.1.3 
Treatment-Emergent Adverse Events 
A treatment emergent adverse event (TEAE) is an AE that occurs or worsens after the first 
dose of trial treatment.  
Where an AE is associated with a partially or fully missing start date or time, and it is unclear 
as to whether the AE is treatment emergent, it will be assumed that it is treatment emergent. 
6.5.9.1.4 
Adverse Event Severity 
All AEs will be categorized as mild, moderate, or severe as directed in the study protocol. 
6.5.9.1.5 
Relationship of Adverse Events to Study Drug 
All AEs will be categorized as related or not related as determined by investigator using these 
explanations as specified in the study protocol: 
• Suspected: A reasonable possibility exists that the investigational product caused the 
AE 
• Not Suspected: A reasonable possibility does not exist that the investigational product 
caused the AE 
 
6.5.9.1.6 
Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator, medical monitor or 
sponsor, it results in any of the following outcomes as specified in the protocol: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 38 of 45 – CONFIDENTIAL 
• Medically important 
 
6.5.9.1.7 
Summaries of Adverse Event 
Treatment-emergent AEs will be summarized. Number of subjects or eyes experiencing a 
TEAE will be summarized by SOC and PT by treatment group and overall. In summary 
tables, SOC will be presented alphabetically and events within SOC will be presented by 
decreasing frequency count based on the total column. 
 
Summary tables (number and percentage of subjects) of AEs will be provided by treatment as 
follows: 
• All treatment-emergent AEs by SOC  
• All treatment-emergent AEs by SOC and PT 
• All treatment-emergent AEs by SOC, PT and maximal severity 
• All treatment-emergent AEs by SOC, PT and strongest relationship 
• All treatment-emergent AEs by SOC, PT, maximal severity, and strongest relationship 
• All serious treatment-emergent AEs by SOC and PT 
• All treatment-emergent AEs leading to premature discontinuation of treatment by 
SOC and PT  
• All non-serious treatment-emergent AEs by SOC and PT occurring at the PT level at 
rates of 1%, 2%, 3%, 4%, and 5% in at least one treatment arm, separately by 
percentage 
 
Separate summaries will be performed for ocular and non-ocular AEs. Ocular AEs will be 
summarized at the subject and eye levels, with separate eye level summaries for study and 
fellow eye. 
 
An overview table will be provided summarizing the number of: 
• TEAEs 
• Serious TEAEs 
• Serious TEAEs by reason for seriousness 
• TEAEs leading to premature discontinuation of treatment 
• TEAEs by worst severity 
• TEAEs by worst relationship 
• TEAEs by pattern 
• TEAEs by outcome 
• TEAEs by action taken 
• TEAEs by action taken related to investigational product 
• TEAE by expected or unexpected status 
 
The treatment groups will be compared in regard to safety endpoints descriptively. No 
inferential comparison will be conducted. 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 39 of 45 – CONFIDENTIAL 
6.5.9.2 
Safety Laboratory Values 
Safety laboratory tests will not be collected. Urine pregnancy test results will be captured at 
Visit 0, Visit 1, and Visit 4. Urine pregnancy test results will be included in a listing. 
6.5.9.3 
Vital Sign Measurements 
Vital signs data will not be collected. 
6.5.9.4 
Other Safety Measurements 
Visual acuity, slit-lamp biomicroscopy, dilated fundoscopy, and intraocular pressure will be 
summarized by treatment group and visit using descriptive statistics in SAF. Changes from 
baseline will also be summarized where appropriate. For assessments performed by eye, 
study eye and fellow eye will be summarized separately. 
6.5.9.4.1 
Visual Acuity 
Visual acuity will be performed at screening, Visits 1-4, and early termination. The base 
logMAR, which is the last line in which a letter is read correctly, and the number of total 
letter missed up to and including the last line read will be collected on the CRF. The 
calculated logMAR will be automatically generated by the EDC as base logMAR + (number 
of total letters missed × 0.02). Descriptive statistics for the calculated LogMAR Score will be 
presented for study eye and fellow eye by treatment and overall at baseline and all post-
baseline visits in the SAF. Changes from baseline will also be summarized.  
6.5.9.4.2 
Slit-lamp Biomicroscopy 
Biomicroscopy will be performed at screening, Visits 1-4, and early termination. 
Observations will be graded as Normal, Abnormal Clinically Significant, or Abnormal Not 
Clinically Significant . Lids, cornea, conjunctiva, anterior chamber, iris and lens will be 
examined. If ‘Check if no changes since Visit 0’ is checked, the results of the tests at Visit 0 
will be used for analysis at that timepoint. Listings will display ‘No changes since Visit 0’. 
Descriptive statistics for the grading by each domain will be presented for study eye and 
fellow eye by treatment and overall at baseline and all post-baseline visits in the SAF. Shifts 
from baseline indicative of worsening will also be summarized. Worsening is defined as a 
shift from normal to abnormal not clinically significant, normal to abnormal clinically 
significant, and abnormal not clinically significant to abnormal clinically significant.  
6.5.9.4.3 
Dilated Fundoscopy Examination 
A dilated fundoscopy examination will be performed during the trial at screening, Visit 4 and 
early termination. Observations will be graded as Normal, Abnormal CS or Abnormal NCS. 
Vitreous, retina, macula, choroid and optic nerve will be examined. If ‘Check if no changes 
since Visit 0’ is checked, the results of the tests at Visit 0 will be used for analysis at that 
timepoint. Listings will display ‘No changes since Visit 0’. Descriptive statistics for the 
grading by each domain will be presented for study eye and fellow eye by treatment and 
overall at baseline and all post-baseline visits in the SAF. Shifts from baseline indicative of 
worsening will also be summarized.  Worsening is defined as a shift from normal to abnormal 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 40 of 45 – CONFIDENTIAL 
not clinically significant, normal to abnormal clinically significant, and abnormal not 
clinically significant to abnormal clinically significant. 
6.5.9.4.4 
Intraocular Pressure 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg at screening, Visit 4 and early 
termination. A single measurement will be made to obtain a determination of IOP. Descriptive 
statistics for the IOP measurement will be presented for study eye and fellow eye by 
treatment and overall at baseline and all post-baseline visits in the SAF. Changes from 
baseline will also be summarized.  
6.5.10 
Determination of Sample Size 
The statistical hypotheses for the primary endpoint of CFB corneal fluorescein staining (NEI 
scale) total score at Day 57 are as follows: 
 
H01: 
The difference, between study eyes treated with NOV03and study eyes treated 
with saline, in the mean CFB corneal fluorescein staining (NEI scale) total score at Day 57 = 
0. 
 
HA1:  The difference, between study eyes treated with NOV03 and study eyes 
treated with saline, in the mean CFB corneal fluorescein staining (NEI scale) total score at 
Day 57 ≠ 0, with superiority claimed if the difference is less than 0 (NOV03 minus saline). 
The statistical hypotheses for the hierarchical primary endpoint of the CFB Dryness Score at 
Day 57 are as follows: 
 
H02: 
The difference, between subjects treated with NOV03 and subjects treated 
with saline, in the mean CFB Dryness Score at Day 57= 0. 
 
HA2:  The difference, between subjects treated with NOV03 and subjects treated 
with saline, in the mean CFB Dryness Score at Day 57 ≠ 0, with superiority claimed if the 
difference is less than 0 (NOV03 minus saline). 
Two hundred fifty (250) subjects (study eyes) per treatment group yields 97.9% power to reject 
H01 in favor of HA1 and conclude superiority of NOV03 over saline in the mean CFB tCFS 
score at Day 57 assuming a true difference (NOV03 minus saline) of -1.0, a common standard 
deviation of 2.8, and a two-sided alpha = 0.05. Two hundred fifty (250) subjects per treatment 
group yields 97.9% power to reject H02 in favor of HA2 and conclude superiority of NOV03 
over saline in the mean CFB Dryness Score (VAS) at Day 57 assuming a true difference 
(NOV03 minus saline) of -10, a common standard deviation of 28, and a two-sided alpha = 
0.05. Accounting for an assumed 10% subject discontinuation rate, approximately 560 subjects 
(280 subject each arm) will be randomly assigned to trial treatment such that approximately 
250 evaluable participants per arm complete the trial. 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 41 of 45 – CONFIDENTIAL 
Therefore, assuming independence between tCFS score and Dryness Score (VAS), 250 FAS 
subjects per treatment group at Day 57 yields 97.9%* 97.9%= 95.8% power to reject both H01 
and H02. A positive correlation between these two endpoints would increase the overall power. 
6.6 
Changes in Planned Analyses 
None.  
7 
INDEX OF PLANNED TABLES, FIGURES, AND LISTINGS 
Tables 
 Number 
Title 
14.1.1.1 
Overall Disposition and Subject Accountability – FAS 
14.1.1.2 
Overall Disposition and Subject Accountability – PPS 
14.1.1.3 
Overall Disposition and Subject Accountability – SAF 
14.1.2.1 
Overview of Analysis Sets – Randomized Subjects  
14.1.2.2 
Reasons for Exclusion from Study Populations – Randomized Subjects 
14.1.3 
Major Protocol Deviations – FAS  
14.1.4.1 
Demographic and Baseline Characteristics – FAS  
14.1.4.2 
Demographic and Baseline Characteristics – PPS 
14.1.4.3 
Demographic and Baseline Characteristics – SAF 
14.1.5.1 
Baseline Ocular Characteristics – FAS  
14.1.5.2 
Baseline Ocular Characteristics – PPS 
14.1.5.3 
Baseline Ocular Characteristics – SAF 
14.1.6.1 
Study Eye Ocular Medical History – FAS  
14.1.6.2 
Fellow Eye Ocular Medical History – FAS  
14.1.6.3 
Subject Level Ocular Medical History – FAS  
14.1.6.4 
Non-ocular Medical History – FAS 
14.1.7.1 
Study Eye Ocular Concomitant Medications – FAS  
14.1.7.2 
Fellow Eye Ocular Concomitant Medications – FAS  
14.1.7.3 
Subject Level Ocular Concomitant Medications – FAS  
14.1.7.4 
Non-ocular Concomitant Medications – FAS  
14.1.8 
Study Medication Exposure and Compliance – SAF 
14.2.1.1 
Analyses of Change from Baseline tCFS and Dryness Score (VAS) at Day 57 – 
FAS  
14.2.1.2 
Analyses of Change from Baseline tCFS and Dryness Score (VAS) at Day 57 – 
PPS 
14.2.2 
Robustness Analyses of Change from Baseline tCFS and Dryness Score (VAS) 
at Day 57 (Discontinuation Rate ≥5%) – FAS 
14.2.3 
Sensitivity Analyses of Change from Baseline tCFS and Dryness Score (VAS) 
at Day 57 – FAS  
14.2.4.1 
Analyses of Secondary Efficacy Endpoints – FAS  
14.2.4.2 
Sensitivity Analyses of Secondary Efficacy Endpoints – FAS  
14.2.5.1 
Analysis of Dryness Score (VAS) – FAS  
14.2.5.2 
Sensitivity Analysis of Dryness Score (VAS) – FAS  
14.2.6.1 
Analysis of Study Eye tCFS – FAS  




Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 43 of 45 – CONFIDENTIAL 
14.3.4.1 
Study Eye Ocular Treatment Emergent Adverse Events by SOC, PT, and 
Maximal Severity – SAF 
14.3.4.2 
Fellow Eye Ocular Treatment Emergent Adverse Events by SOC, PT, and 
Maximal Severity – SAF 
14.3.4.3 
Non-ocular Treatment Emergent Adverse Events by SOC, PT, and Maximal 
Severity – SAF 
14.3.5.1 
Study Eye Ocular Treatment Emergent Adverse Events by SOC, PT, and 
Strongest Relationship – SAF 
14.3.5.2 
Fellow Eye Ocular Treatment Emergent Adverse Events by SOC, PT, and 
Strongest Relationship – SAF 
14.3.5.3 
Non-ocular Treatment Emergent Adverse Events by SOC, PT, and Strongest 
Relationship – SAF 
14.3.6.1 
Study Eye Ocular Treatment Emergent Adverse Events by SOC, PT, Maximal 
Severity, and Strongest Relationship – SAF 
14.3.6.2 
Fellow Eye Ocular Treatment Emergent Adverse Events by SOC, PT, Maximal 
Severity, and Strongest Relationship – SAF 
14.3.6.3 
Non-ocular Treatment Emergent Adverse Events by SOC, PT, Maximal 
Severity, and Strongest Relationship – SAF 
14.3.7.1 
Study Eye Ocular Serious Treatment Emergent Adverse Events by SOC and PT 
– SAF 
14.3.7.2 
Fellow Eye Ocular Serious Treatment Emergent Adverse Events by SOC and 
PT – SAF 
14.3.7.3 
Non-ocular Serious Treatment Emergent Adverse Events by SOC and PT – 
SAF 
14.3.8.1 
Study Eye Ocular Treatment Emergent Adverse Events Leading to Premature 
Discontinuation of Treatment by SOC and PT – SAF 
14.3.8.2 
Fellow Eye Ocular Treatment Emergent Adverse Events Leading to Premature 
Discontinuation of Treatment by SOC and PT – SAF 
14.3.8.3 
Non-ocular Treatment Emergent Adverse Events Leading to Premature 
Discontinuation of Treatment by SOC and PT – SAF 
14.3.9.1 
Study Eye Ocular Non-serious Treatment Emergent Adverse Events by SOC 
and PT Occurring at the PT Level at Rates of 1%, 2%, 3%, 4%, and 5% in at 
Least one Treatment Arm – SAF  
14.3.9.2 
Fellow Eye Ocular Non-serious Treatment Emergent Adverse Events by SOC 
and PT Occurring at the PT Level at Rates of 1%, 2%, 3%, 4%, and 5% in at 
Least one Treatment Arm – SAF 
14.3.9.3 
Non-ocular Non-serious Treatment Emergent Adverse Events by SOC and PT 
Occurring at the PT Level at Rates of 1%, 2%, 3%, 4%, and 5% in at Least one 
Treatment Arm – SAF 
14.4.1.1 
Summary of Study Eye BCVA (logMAR) Results and Change from Baseline by 
Visit - SAF 
14.4.1.2 
Summary of Fellow Eye BCVA (logMAR) Results and Change from Baseline 
by Visit - SAF 
14.4.2.1 
Summary of Study Eye Slit-lamp Biomicroscopy Results by Location and Visit 
– SAF 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 44 of 45 – CONFIDENTIAL 
14.4.2.2 
Summary of Fellow Eye Slit-lamp Biomicroscopy Results by Location and 
Visit – SAF 
14.4.3.1 
Worsening Shifts in Study Eye Slit-lamp Biomicroscopy Results– SAF  
14.4.3.2 
Worsening Shifts in Fellow Eye Slit-lamp Biomicroscopy Results– SAF  
14.4.4.1 
Summary of Study Eye Dilated Fundoscopy Results by Location and Visit – 
SAF 
14.4.4.2 
Summary of Fellow Eye Dilated Fundoscopy Results by Location and Visit – 
SAF 
14.4.5.1 
Worsening Shifts in Study Eye Dilated Fundoscopy Results– SAF 
14.4.5.2 
Worsening Shifts in Fellow Eye Dilated Fundoscopy Results– SAF 
14.4.6.1 
Summary of Study Eye Intraocular Pressure and Change from Baseline by Visit 
– SAF  
14.4.6.2 
Summary of Fellow Eye Intraocular Pressure and Change from Baseline by 
Visit – SAF  
Listings 
16.2.1 
Subject Disposition 
16.2.2.1 
Inclusion Criterion  
16.2.2.2 
Exclusion Criterion 
16.2.2.4 
Protocol Deviations 
16.2.3.1 
Subjects Excluded from the Per Protocol Analysis Set 
16.2.4.1 
Demographic and Baseline Information 
16.2.4.2 
Ocular Medical History 
16.2.4.3 
Ocular Surgical History 
16.2.4.4 
Non-ocular Medical History 
16.2.4.5 
Non-ocular Surgical History 
16.2.5.1 
Dosing Compliance and Exposure 
16.2.5.2 
Dispense Investigational Drug 
16.2.5.3 
Daily Dosing Diary 
16.2.5.4 
Randomized and Actual Treatments 
16.2.6.1 
Corneal Fluorescein Staining (CFS) by Area and Total Score 
16.2.6.2 
Dryness Score (VAS) 
16.2.6.3 
Ocular Symptoms (VAS) 
16.2.6.4 
Ocular Surface Disease Index (OSDI) 
16.2.6.5 
Meibomian Gland Assessment (MGD Score) 
16.2.6.6 
Schirmer’s Test I (Without Anesthesia) 
16.2.6.7 
Tear Film Break-up Time (TFBUT) 
16.2.6.8 
Instillation Comfort Questionnaire 
16.2.6.9 
Eyedrop Acceptability Questionnaire 
16.2.6.10 Collection of Returned Investigational Product 
16.2.7.1 
All Adverse Events by SOC, PT, and Verbatim Term 
16.2.7.2 
Adverse Events Leading to Premature Discontinuation of Treatment 
16.2.7.3 
Serious Adverse Events 
16.2.7.4 
Subject Deaths 
16.2.8.1 
Pregnancy Test 
16.2.9.1 
Visual Acuity 


Statistical Analysis Plan Version 1.0 Dated 17 December 2020 
Protocol Number: 904 
 
Page 45 of 45 – CONFIDENTIAL 
16.2.9.2 
Slit-lamp Biomicroscopy 
16.2.9.3 
Dilated Fundoscopy 
16.2.9.4 
Intraocular Pressure 
16.2.9.5 
Ocular Concomitant Medications 
16.2.9.6 
Ocular Concomitant Therapies 
16.2.9.7 
Non-ocular Concomitant Medications 
16.2.9.8 
Non-ocular Concomitant Therapies 
16.3.1 
Unscheduled Visits 
16.3.2 
Subject Completion 
 
8 
REFERENCES 
 

Prot_001.pdf: 
NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb Incorporated 
Clinical Trial Protocol #904 
09NOV2020 FINAL v2.0 
Confidential 
Page 1 of 75 
Clinical Trial Protocol 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Saline-Controlled Trial to Evaluate the Effect of NOV03 
(Perfluorohexyloctane) on Signs and Symptoms of Dry 
Eye Disease Associated with Meibomian Gland 
Dysfunction (Mojave Study) 
Protocol Number: 
904 
Trial Phase: 
3 
Investigational 
Product 
Name: 
NOV03 (100% perfluorohexyloctane) 
IND Number: 
IND 130558 
Indication: 
Dry Eye Disease (keratoconjunctivitis sicca) 
 
  
Investigators: 
Multi-Center 
Sponsor: 
Bausch & Lomb, Incorporated  
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
USA  
Clinical Research 
Organisation: 
IRB/IEC: 
Sterling IRB 
Version: 
2.0 
Original Protocol Date: 
05 AUG 2020 
Amendment 1 Date 
09 NOV 2020 
________________________________________________________________________ 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Bausch & Lomb, Inc. 
Further dissemination, distribution or copying of this protocol or its contents is strictly 
prohibited. 
Regulatory Statement 
This trial will be performed in compliance with the protocol and in accordance with Good 
Clinical Practice (International Conference on Harmonisation [ICH], Guidance E6), 
principles of human subject protection, and applicable country-specific regulatory 
requirements. 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb Incorporated 
Clinical Trial Protocol #904 
09NOV2020 FINAL v2.0 
 
Confidential 
Page 2 of 75 
1 SYNOPSIS AND TRIAL CONTACT INFORMATION 
 
1.1 TRIAL CONTACT INFORMATION 
SPONSOR PERSONNEL 
 
 
 
  
 
  
 
 
MEDICAL MONITOR 
Clinical Research Organization (CRO) PERSONNEL 
 
 
 
 
1.2 SYNOPSIS 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-
Masked, Saline-Controlled Trial to Evaluate the 
Effect of NOV03 (Perfluorohexyloctane) on Signs 
and Symptoms of Dry Eye Disease Associated with 
Meibomian Gland Dysfunction (Mojave Study) 
Protocol Number: 
904 
Investigational Medicinal 
Product: 
NOV03 (100% perfluorohexyloctane) 
Control: 
Saline solution: 0.6% sodium chloride solution  
Trial Phase: 
3 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb Incorporated 
Clinical Trial Protocol #904 
09NOV2020 FINAL v2.0 
 
Confidential 
Page 3 of 75 
Trial Objective: 
The objectives of this trial are to assess the efficacy, 
safety, and tolerability of NOV03 ophthalmic 
solution in comparison to a saline control for the 
treatment of the signs and symptoms of Dry Eye 
Disease (DED) 
 
 
Overall Trial Design 
 
Structure: 
Multi-center, randomized, double-masked, saline-
controlled 
Participant Duration: 
An individual subject’s participation is estimated to 
be approximately 10 weeks. 
Trial Duration: 
The estimated trial duration is approximately 7 
months, from first subject first visit to last subject 
last visit. 
Dosage/Dose Regimen: 
Subjects eligible for randomization will receive one 
of the following treatments to be administered 
bilaterally from Visit 1 to Visit 4. 
1) NOV03 (100% perfluorohexyloctane)  
4 times daily (QID)  
2) Saline solution (0.6% sodium chloride solution) 
4 times daily (QID) 
Summary of Visit Schedule: 
5 visits over the course of approximately 10 weeks 
• Visit 0 = Screening within 14 days before Visit 1 
(Day -14 to -1) 
• Visit 1 = Day 1, Baseline/Randomization 
• Visit 2 = Day 15 ± 1 days, 
• Visit 3 = Day 29 ± 2 days 
• Visit 4 = Day 57 ± 2 days 
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, double-
masked, multi-center trial. Subjects will be 
instructed not to show or discuss the properties of the 
assigned Investigational Medicinal Product (IMP) 
and/or their experience with the IMP with other trial 
participants, and not to show or discuss the IMP with 
the Investigator or site staff other than the dedicated 
dosing coordinator, unless instructed to do so. 
 
A dedicated dosing coordinator at each site will be 
responsible for instructing subjects regarding IMP 
handling/administration, IMP dispensation and 
accountability, reviewing daily dosing diaries, 
performing the instillation comfort questionnaire, 
the Eyedrop acceptability questionnaire and all 
discussions with study subjects related to IMP. 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb Incorporated 
Clinical Trial Protocol #904 
09NOV2020 FINAL v2.0 
 
Confidential 
Page 4 of 75 
Trial Population Characteristics 
Number of Subjects: 
Approximately 760 subjects will be screened to 
enroll at least 560 subjects (280 each arm) at 
approximately 35 clinical sites. 
Condition/Disease: 
Dry Eye Disease (keratoconjunctivitis sicca) 
associated with Meibomian Gland Dysfunction 
Inclusion Criteria: 
Subjects must: 
1. Be at least 18 years of age at the time of consent. 
2. Provide written informed consent. 
3. Have a subject reported history of Dry Eye 
Disease in both eyes for at least 6 months prior 
to Visit 0. 
4. Have Tear film break-up time (TFBUT) ≤5 sec 
at Visit 0 and Visit 1. 
5. Have Ocular Surface Disease Index (OSDI©) 
≥25 at Visit 0 and Visit 1. 
6. Have an unanesthetized Schirmer’s Test I ≥5 
mm at Visit 0 and Visit 1. 
7. 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 0 and Visit 1. 
8. Have a total corneal fluorescein staining score 
of 4 ≤ X ≤11 (i.e. sum of inferior, superior, 
central, nasal, and temporal) according to the 
National Eye Institute (NEI) scale at Visit 0 and 
Visit 1. 
9. Have at least one eye (the same eye) satisfy all 
criteria for 4, 6, 7, and 8 above at Visit 0 and 
Visit 1. 
10. Be able and willing to follow instructions, 
including participation in all trial assessments 
and visits. 
Exclusion Criteria: 
Subjects must not: 
1. Have been randomized in NVU-002, NVU-003, 
or participated in the NVU-004 OLE Study. 
2. Have any clinically significant ocular surface 
slit-lamp findings at Visit 0 and Visit 1 and/or in 
the opinion of the investigator have any findings 
that may interfere with trial parameters and may 
include eye trauma or history of eye trauma or 
anterior membrane dystrophy. 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb Incorporated 
Clinical Trial Protocol #904 
09NOV2020 FINAL v2.0 
 
Confidential 
Page 5 of 75 
3. Have a history of Stevens Johnson Syndrome. 
4. Have 
active 
blepharitis 
or 
lid 
margin 
inflammation 
that 
required 
any 
topical 
antibiotics or topical steroids within last 30 days 
prior to Visit 0 or will likely require such 
treatment during the trial. Any other lid margin 
therapy such as lid scrubs, lid wipes, warm 
compresses, systemic antibiotics (such as 
tetracyclines) and oral supplements for treatment 
of ocular conditions had to be stable within the 
last 30 days prior to Visit 1 and should be 
maintained stable throughout the trial.  
5. Have had a LipiFlow procedure, Intense Pulse 
Light (IPL) procedure or any kind of other 
procedures affecting meibomian glands within 6 
months prior to Visit 1. 
6. Have abnormal lid anatomy that causes 
incomplete eyelid closure including entropion 
and ectropion or floppy lid syndrome that 
exposes parts of the conjunctiva or impairs the 
blinking function of the eye (e.g. Botox 
injections for blepharospasm). 
7. Have received or removed a permanent punctum 
plug within 3 months (6 months for dissolvable 
punctum plugs) prior to Visit 1 or expected to 
receive a punctum plug or removal of a punctum 
plug, or a punctum plug expected to be dissolved 
during the trial.  
8. Have Dry Eye Disease secondary to scarring, 
irradiation, alkali burns, cicatricial pemphigoid, 
or destruction of conjunctival goblet cells (as 
with vitamin A deficiency). 
9. Have an ocular or periocular malignancy.   
10. Have a corneal epithelial defect; have significant 
confluent staining or filaments anywhere on the 
cornea.  
11. Have a history of herpetic keratitis. 
12. Have active ocular allergies or ocular allergies 
that are expected to be active during the trial 
period. 
13. Be diagnosed with an active ocular or systemic 
infection (bacterial, viral, or fungal), including 
fever requiring treatment with antibiotics. 
14. Have worn contact lenses within 1 month of 
Visit 0 or anticipate using contact lenses during 
the trial. 


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15. Have used any eye drops and/or TrueTearTM 
device (Intranasal Tear Neurostimulator) within 
24 hours before Visit 1. 
16. Have had intra-ocular surgery or ocular laser 
surgery within the previous 6 months or have 
any planned ocular and/or lid surgeries over the 
trial period. 
17. Be a family member living in the same 
household of another randomized study 904 or 
NVU-003 subject, or a family member living in 
the same household of another NVU-004 OLE 
participant. 
18. Be a clinical site employee that is directly 
involved in the management, administration, or 
support of this trial or be an immediate family 
member of the same.  
19. Be a woman who is pregnant, nursing or 
planning a pregnancy. 
20. Be unwilling to submit to a urine pregnancy test 
at Visit 0, Visit 1 and Visit 4 (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 bilateral tubal ligation or 
bilateral oophorectomy) or is post-menopausal 
(without menses for 12 consecutive months). 
21. 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 
(IUD); 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 trial, she must agree to use adequate 
birth control as defined above for the remainder 
of the trial. 
22. Have an uncontrolled systemic disease in the 
opinion of the investigator. 
23. Have a known allergy and/or sensitivity to the 
investigational drug or saline components.  


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24. Have active ocular or periocular rosacea that in 
the judgement of the investigator interferes with 
the trial (e.g, clinically relevant lid induration).  
25. Have a pterygium in any eye.  
26. Be currently enrolled in an investigational drug 
or device study or have used an investigational 
drug or device within 60 days of Visit 1. 
27. Have used any topical ocular steroids treatments, 
topical cyclosporine, lifitegrast, serum tears or 
topical anti-glaucoma medication within 60 days 
prior to Visit 0. 
28. Have 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 0 or expected to be 
unstable during the trial. 
29. Have corrected visual acuity worse than or equal 
to logarithm of the minimum angle of resolution 
(logMAR), +0.7 as assessed with Early 
Treatment of Diabetic Retinopathy Study 
(ETDRS) charts in both eyes at Visit 0 and 
Visit 1. 
30. Have a condition or be in a situation (including 
language barrier) which the investigator feels 
may put the subject at significant risk, may 
confound the trial results, or may interfere 
significantly with the subject’s participation in 
the trial. 
31. Have a history of isotretinoin (e.g. Accutane, 
Myorisan, Claravis, Amnesteem) use. 
Trial Formulations: 
• 100% Perfluorohexyloctane  
• Saline Solution (0.6% sodium chloride solution) 
Evaluation Criteria 
 
Efficacy Endpoint(s):  
Primary Efficacy Endpoints: 
The following primary endpoints will be tested 
using a hierarchical fixed sequence testing to 
maintain an overall two-sided alpha = 0.05 level: 
 
1. Change from baseline (CFB) in total Corneal 
Fluorescein Staining (tCFS) (NEI scale) at 
Day 57 
2. CFB of Dryness Score (visual analogue scale 
[VAS] Severity of Dryness) at Day 57 
 
Secondary Efficacy Endpoints: 


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If both primary endpoints demonstrate statistically 
significant superiority of NOV03 versus saline at the 
two-sided alpha = 0.05 level, the following 
secondary endpoints will be tested hierarchically to 
maintain an overall two-sided alpha = 0.05. 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining 
(tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining 
(cCFS) (NEI scale) at Day 57 
 
Other Pre-specified Efficacy Endpoints 
1. CFB of Dryness Score (VAS) at Day 29  
2. CFB in tCFS at Day 29  
3. CFB in CFS central and inferior sub-regions 
(NEI scale) to each measured post-baseline visit. 
4. Proportion of tCFS responders (≥3 improvement 
based on NEI scale) at Day 57. 
5. Proportion of Dryness Score responders (≥30 % 
improvement from baseline) at Day 57. 
6. CFB in VAS burning/stinging, sticky feeling, 
foreign body sensation, itching, blurred vision, 
sensitivity to light, pain, frequency of dryness, 
and awareness of dry eye symptoms at each 
measured post-baseline visit. 
7. CFB in Ocular Surface Disease Index (OSDI©) 
at each measured post-baseline visit. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Safety Endpoints: 
1. Ocular and non-ocular Treatment Emergent 
Adverse Events (TEAEs) 
2. Visual Acuity 
3. Slit-Lamp Biomicroscopy  
4. Intraocular Pressure  
5. Dilated Fundoscopy  
 
 
 
 
 
General Statistical Methods and Types of Analyses 


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The primary endpoints will be tested in a hierarchical fixed sequence in the following 
order. 
 
The statistical hypotheses for the primary endpoint of CFB corneal fluorescein 
staining (NEI scale) total score at Day 57 are as follows: 
 
H01: 
The difference, between study eyes treated with NOV03 and study 
eyes treated with saline, in the mean CFB corneal fluorescein staining 
(NEI scale) total score at Day 57 = 0. 
 
HA1:  The difference, between study eyes treated with NOV03 and study 
eyes treated with saline, in the mean CFB corneal fluorescein staining 
(NEI scale) total score at Day 57 ≠ 0, with superiority claimed if the 
difference is less than 0 (NOV03 minus saline). 
 
The statistical hypotheses for the hierarchical primary endpoint of the CFB Dryness 
Score (VAS) at Day 57 are as follows: 
 
H02: 
The difference, between subjects treated with NOV03 and subjects 
treated with saline, in the mean CFB Dryness Score (VAS) at Day 57= 
0. 
 
HA2: 
The difference, between subjects treated with NOV03 and subjects 
treated with saline, in the mean CFB Dryness Score (VAS) at Day 57 ≠ 
0, with superiority claimed if the difference is less than 0 (NOV03 
minus saline). 
The study has been designed to have 95% power to reject both H01 and H02 assuming 
independence between the sign and symptom endpoint; positive correlation between 
these two endpoints would increase the overall power. 
Estimated mean differences (common standard deviations) in CFB to Day 57 using an 
ANCOVA analysis with CFB to Day 57 as the response, baseline as a covariate and 
treatment as the fixed effect from NVU-002 are: -1.2 (2.5) for tCFS and -11 (26) for 
Dryness Score. Conservative estimates of -1.0 (2.8) for tCFS and -10 (28) for Dryness 
Score are used for sample size calculation. 
 
Two hundred fifty (250) subjects (study eyes) per treatment group yields 97.9% power 
to reject H01 in favor of HA1 and conclude superiority of NOV03 over saline in the mean 
CFB tCFS score at Day 57 assuming a true difference (NOV03 minus saline) of -1.0, a 
common standard deviation of 2.8, and a two-sided alpha = 0.05. Two hundred fifty 
(250) subjects per treatment group yields 97.9% power to reject H02 in favor of HA2 and 
conclude superiority of NOV03 over saline in the mean CFB Dryness Score (VAS) at 
Day 57 assuming a true difference (NOV03 minus saline) of -10, a common standard 
deviation of 28, and a two-sided alpha = 0.05. Accounting for an assumed 10% subject 
discontinuation rate, approximately 560 subjects (280 subject each arm) will be 


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randomly assigned to trial treatment such that approximately 250 evaluable participants 
per arm complete the trial. 
 
Therefore, assuming independence between tCFS score and Dryness Score (VAS), 250 
FAS subjects per treatment group at Day 57 yields 97.9%* 97.9%= 95.8% power to 
reject both H01 and H02. 
 
Hierarchical fixed sequence testing will be employed to maintain the type I error rate. 
The primary analyses will first test the difference in the mean CFB corneal fluorescein 
staining (NEI scale) total score between treatments at Day 57. If the test of the 
difference is statistically significant at the two-sided alpha = 0.05 level in favor of 
NOV03 then the trial will be considered a success; NOV03 will be declared to be 
superior to saline in the mean CFB corneal fluorescein staining (NEI scale) total score 
at Day 57; and the difference in the mean CFB total Dryness Score between treatments 
at Day 57 will be tested at the two-sided alpha = 0.05 level. 
 
If in addition to a statistically significant test of the difference in the mean CFB corneal 
fluorescein staining (NEI scale) total score at Day 57 is in favor of NOV03, and the test 
of the difference in the mean change from Dryness Score at Day 57 is also statistically 
significant in favor of NOV03, then NOV03 will be declared to be superior to saline in 
both the mean CFB corneal fluorescein staining (NEI scale) total score and the mean 
CFB of the Dryness Score at Day 57. 
 
If both primary endpoints demonstrate statistically significant superiority of NOV03 
versus saline at the two-sided alpha = 0.05 level, a hierarchical testing of the secondary 
endpoints will be performed.  
 
Primary Efficacy Analyses:  
The primary comparison in this trial will be between NOV03 versus saline at Day 57. 
The primary efficacy endpoints (e.g. CFB in total corneal fluorescein staining [NEI 
scale] and Dryness Score [VAS]) will be summarized descriptively (n, mean, standard 
deviation, median, min, and max) and analyzed separately using an ANCOVA model 
with terms for baseline value, and treatment. 
Least squares mean for each treatment group and for the difference between treatment 
groups will be presented from each model together with two-sided p-values (used for 
primary inference) and 95% confidence intervals. 
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures 
analysis comparing treatment groups will be performed as sensitivity analyses. 
The primary analysis of the primary endpoints will use the Full Analysis Set (FAS) 
with available data per subject, assuming the overall study discontinuation rate is <5%. 
If the overall study discontinuation rate is ≥5% then the primary analysis will be based 
on primary imputation methodology as detailed in the statistical analysis section and 
the available data analyses will become robustness analyses. 


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Additional robustness analyses will include repeating the primary analysis on the per 
protocol set (PPS); the FAS imputing missing data using last observation carried 
forward (LOCF); the FAS imputing missing data using Markov Chain Monte Carlo 
(MCMC) multiple imputation methodology under different assumptions of 
missingness (at random and not at random) each using 30 imputed values.  
 
Further Efficacy Analyses: 
The following secondary endpoints will be tested hierarchically: 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
 
Inference will only be made on these endpoints, at a 2-sided alpha = 0.05, if both 
primary endpoints and any higher order secondary endpoints are statistically significant 
at a 2-sided alpha = 0.05 in favor of NOV03. 
 
The primary analysis of the secondary endpoints will use the Full Analysis Set (FAS) 
with available data per subject, assuming the overall study discontinuation rate is <5%. 
If the overall study discontinuation rate is ≥5%, then the primary analysis of the 
secondary endpoints will follow the same imputation strategy detailed for the primary 
endpoints. 
Quantitative secondary and other pre-specified efficacy endpoints will be summarized 
descriptively (n, mean, standard deviation, median, min and max) by visit, and analyzed 
similarly to the primary endpoint at each measured visit and CFB. Least squares mean 
for each treatment group and for the difference between treatment groups will be 
presented from the model together with two-sided p-values and 95% confidence 
intervals.  
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures 
analysis will also be presented as sensitivity analyses. The other pre-specified analyses 
will use the Full Analysis Set (FAS) with available data per subject. 
Other pre-specified endpoints evaluating the proportion of study eyes (or subjects) 
meeting pre-defined criteria will be presented and tested between treatment groups 
using logistic regression analysis adjusting for baseline tCFS score at each measured 
follow-up visit. Pearson chi-squared analysis comparing the treatment groups will be 
performed as sensitivity analyses.  
 
Safety Variables: 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and 
percentages of subjects with treatment-emergent adverse events (TEAEs), serious 
TEAEs, and TEAEs causing premature discontinuation will be provided by treatment 


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group. An AE is treatment emergent if it occurs or worsens after the first dose of trial 
treatment. Furthermore, frequencies will be given of subjects with TEAEs by system 
organ class; by system organ class and preferred term; by system organ class, preferred 
term and maximal severity; by system organ class, preferred term and strongest 
relationship; and by system organ class, preferred term, maximal severity, and strongest 
relationship. Separate summaries will be performed for ocular and non-ocular TEAEs. 
Other safety endpoints including assessments of visual acuity, slit-lamp biomicroscopy, 
dilated fundoscopy, and intraocular pressure will be summarized by treatment group 
and visit using descriptive statistics. Changes from baseline will also be summarized 
where appropriate. For assessments performed by eye, study eye and fellow eye will 
be summarized separately.  
 
 
 


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TABLE OF CONTENTS 
 
1 
SYNOPSIS AND TRIAL CONTACT INFORMATION ..................................... 2 
1.1 
TRIAL CONTACT INFORMATION .................................................................. 2 
1.2 
SYNOPSIS............................................................................................................... 2 
TABLE OF CONTENTS................................................................................................ 13 
LIST OF ABBREVIATIONS ........................................................................................ 17 
2 
INTRODUCTION .................................................................................................. 19 
2.1 
Dry Eye Disease (DED) ........................................................................................ 19 
2.2 
Product Rationale ................................................................................................. 19 
2.3 
Trial Rationale ...................................................................................................... 20 
2.4 
Summary of Known and Potential Risks and Benefits to Human Subjects ... 21 
3 
TRIAL OBJECTIVES ........................................................................................... 22 
3.1 
Primary Objective ................................................................................................ 22 
3.2 
Secondary Objectives ........................................................................................... 22 
4 
TRIAL DESIGN ..................................................................................................... 22 
4.1 
Overall Trial Design ............................................................................................. 22 
4.2 
End of Trial Definition ......................................................................................... 23 
4.3 
Visit Description ................................................................................................... 23 
4.4 
Enrollment and Treatment Assignment ............................................................. 24 
4.5 
Justification of Trial Design ................................................................................ 25 
4.6 
Justification of Dose ............................................................................................. 26 
5 
TRIAL POPULATION ......................................................................................... 26 
5.1 
Number of Subjects (approximate) ..................................................................... 26 
5.2 
Trial population characteristics .......................................................................... 26 
5.3 
Inclusion Criteria.................................................................................................. 26 
5.4 
Exclusion Criteria ................................................................................................. 27 
5.5 
Re-Screen Procedures .......................................................................................... 29 
5.6 
Subject/Trial Withdrawal Criteria ..................................................................... 29 
6 
TRIAL PARAMETERS ........................................................................................ 30 
6.1 
Efficacy Endpoints................................................................................................ 30 
6.1.1 
Primary Efficacy Endpoints: ............................................................ 30 
6.1.2 
Secondary Efficacy Endpoints: ........................................................ 30 
6.1.3 
Other Pre-specified Efficacy Endpoints:.......................................... 30 
6.1.4 
Exploratory Efficacy Endpoints: ...................................................... 30 
6.2 
Safety Endpoints ................................................................................................... 31 
6.3 
Other Endpoints ................................................................................................... 31 
7 
TRIAL MATERIALS ............................................................................................ 32 
7.1 
Investigational Medicinal Product(s) .................................................................. 32 
7.1.1 
IMP(s)/ Formulation (s) ................................................................... 32 
7.1.2 
Labeling and Packaging of IMP....................................................... 32 
7.1.3 
IMP Storage ..................................................................................... 33 
7.1.4 
IMP Dispensation ............................................................................. 33 
7.1.5 
Instructions for Use and Administration .......................................... 33 


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7.2 
IMP Accountability .............................................................................................. 34 
7.3 
IMP Handling and Return ................................................................................... 35 
7.4 
IMP Masking ........................................................................................................ 35 
7.5 
Other Trial Supplies ............................................................................................. 35 
8 
TRIAL METHODS AND PROCEDURES ......................................................... 36 
8.1 
Concurrent Medications and Therapies ............................................................. 36 
8.2 
Prohibited Medications ........................................................................................ 36 
8.3 
Restrictions and Prohibitions .............................................................................. 37 
8.4 
Examination Procedures ...................................................................................... 37 
8.4.1 
Procedures to be performed at each trial visit with regard to trial 
objective(s) .................................................................................................... 37 
8.4.2 
Early Termination/Discontinuation.................................................. 39 
8.4.3 
Unscheduled Visits .......................................................................... 40 
8.5 
Compliance with Protocol .................................................................................... 40 
8.6 
Subject Disposition ............................................................................................... 40 
8.6.1 
Completed Subjects.......................................................................... 40 
8.6.2 
Discontinued subjects ...................................................................... 41 
8.7 
Trial Termination ................................................................................................. 41 
8.8 
Trial Duration ....................................................................................................... 41 
9 
ADVERSE EVENTS.............................................................................................. 42 
9.1 
Adverse Event ....................................................................................................... 42 
9.1.1 
Severity ............................................................................................ 42 
9.1.2 
Relationship to Investigational Product ........................................... 43 
9.1.3 
Expectedness .................................................................................... 43 
9.1.4 
Outcome ........................................................................................... 43 
9.2 
Serious Adverse Events ........................................................................................ 44 
9.3 
Procedures for Reporting Serious Adverse Events ........................................... 45 
9.3.1 
Reporting a Serious Adverse Event ................................................. 45 
9.3.2 
Reporting a Suspected Unexpected Serious Adverse Reaction 
(SUSAR)........................................................................................................ 46 
9.4 
Procedures for Unmasking of IMP ..................................................................... 46 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events .......... 46 
9.6 
Reporting Pregnancies ......................................................................................... 47 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ............... 48 
10.1 Analysis Populations ............................................................................................ 48 
10.2 Statistical Hypotheses ........................................................................................... 48 
10.3 Sample Size............................................................................................................ 49 
10.4 Statistical Analysis ................................................................................................ 50 
10.4.1 General Considerations .................................................................... 50 
10.4.2 Unit of Analysis ............................................................................... 50 
10.4.3 Missing Data .................................................................................... 50 
10.4.4 Multiplicity Consideration ............................................................... 51 
10.4.5 Primary Efficacy Analyses............................................................... 51 
10.4.6 Secondary Efficacy Analyses........................................................... 53 
10.4.7 Other Pre-specified Efficacy Analyses ............................................ 53 
10.4.8 Exploratory Analyses ....................................................................... 54 
10.4.9 Other Analyses ................................................................................. 54 


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10.4.10 Safety Variables Analyses ............................................................... 54 
10.4.11 Interim Analyses .............................................................................. 55 
10.5 Additional Analyses .............................................................................................. 55 
10.6 Methods to Minimize Bias ................................................................................... 55 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ............................... 56 
11.1 Protection of Human Subjects ............................................................................. 56 
11.1.1 Subject Informed Consent ................................................................ 56 
11.1.2 Institutional Review Board (IRB) Approval .................................... 56 
11.2 Ethical Conduct of the Trial ................................................................................ 56 
11.3 Subject Confidentiality ........................................................................................ 56 
11.4 Documentation ...................................................................................................... 57 
11.4.1 Retention of Documentation ............................................................ 57 
11.5 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) .................................................................................................................. 57 
11.6 Monitoring and Quality Assurance .................................................................... 58 
11.7 Handling of Biological Specimens ....................................................................... 58 
11.8 Publications ........................................................................................................... 58 
12 
REFERENCES ....................................................................................................... 59 
13 
APPENDICES ........................................................................................................ 60 
Appendix 1 Schedule of Assessments (in recommended order) ................................. 60 
Appendix 2 Instructions for Administration of Eye Drops ......................................... 61 
Appendix 3 Examination Procedures, Tests, Equipment, and Techniques ............... 63 
Appendix 4 Amendment Summary of Changes ........................................................... 73 
Appendix 5 Sponsor and CRO Approvals .................................................................... 74 
Appendix 6 Investigator’s Signature ............................................................................. 75 
 
 
 
 


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LIST OF TABLES 
 
Table 1 
Active Investigational Product ....................................................................... 32 
Table 2 
Control Investigational Product ...................................................................... 32 
 
 
LIST OF FIGURES 
Figure 1 
Study 904 Flow Chart ..................................................................................... 24 
 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Assessments (in recommended order)........................................ 60 
Appendix 2 Instructions for Administration of Eye Drops ................................................ 61 
Appendix 3 Examination Procedures, Tests, Equipment, and Techniques ....................... 63 
Appendix 4 Amendment Summary of Changes ................................................................ 73 
Appendix 5 Sponsor and CRO Approvals ......................................................................... 74 
Appendix 6 Investigator’s Signature.................................................................................. 75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCVA 
Best-corrected Visual Acuity 
BID 
Two times daily 
BOCF 
Baseline Observation Carried Forward 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CFS 
Corneal Fluorescein Staining 
cCFS 
Central Corneal Fluorescein Staining 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
DED 
Dry Eye Disease 
DEWS 
Dry Eye Workshop 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capturing system 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug  
IOP 
Intraocular Pressure 
IRB 
Institutional/Independent Review Board 
IPL 
Intense Pulse Light 
IUD 
Intra-Uterine Device 
IRS 
Interactive Response System 
logMAR 
logarithm of the Minimum Angle of Resolution 
LOCF 
Last Observation Carried Forward 
LSLV 
Last Subject Last Visit 
MCMC 
Markov Chain Monte Carlo  
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
Meibomian Gland Dysfunction 
NEI 
National Eye Institute 
NOV03 
100% perfluorohexyloctane 
OD 
right eye 
OS 
left eye 
OSDI© 
Ocular Surface Disease Index 


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PPS 
Per Protocol Set 
QID 
Four times a day 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SMP 
Safety Management Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAEs 
Treatment-emergent Adverse Events 
tCFS 
total Corneal Fluorescein Staining 
TFBUT 
Tear Film Break-up Time 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
 
 


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2 INTRODUCTION 
2.1 Dry Eye Disease (DED) 
Dry Eye Disease (DED) is defined by the International Dry Eye Workshop (DEWS) as a 
multifactorial disease of the ocular surface characterized by a loss of homeostasis of the 
tear film, and accompanied by ocular symptoms, in which tear film instability and 
hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities 
play etiological roles (Craig et al., 2017). Symptoms of DED such as feeling of dryness, 
burning, a sandy/gritty sensation, foreign body sensation, pain or itchiness are quite 
debilitating. In addition, visual function related symptoms such as fluctuating vision with 
blinking, blurred vision, and difficulty with reading despite perfect visual acuity is an 
important and underestimated aspect of the disease. In consequence, DED negatively 
impacts quality of life comparably to other severe diseases (Schiffman et al., 2003), and 
adverse effects on mental health, such as depression and anxiety, have been observed (Le 
et al., 2012). DED is a serious and chronic disorder that, if left untreated or undertreated, 
progressively damages the ocular surface and may lead to permanent vision loss due to 
corneal complications (Lemp et al., 1995). 
 
As many as 5 - 35% of subjects visiting ophthalmic clinics report dry eye symptoms, 
making it one of the most common conditions seen by ophthalmic specialists (McCarty et 
al., 1998; Lin et al., 2003). Estimates of the prevalence of dry eye vary considerably, 
depending on the criteria used to define the disease, but in the United States (US), it has 
been estimated that as many as 3.2 million women and 1.7 million men over the age of 50 
have DED, with a projected 40% increase in the number of patients affected by 2030 
(Schaumberg et al., 2002; Schaumberg et al., 2003; Schaumberg et al., 2009) With the aging 
population in the US and other countries of the developed world, and with increasing 
computer use, DED is expected to continue to become more prevalent and finding a 
treatment is becoming more important (Benitez-del-Castillo et al., 2017).  
2.2 Product Rationale 
NOV03 is a sterile ophthalmic eye drop formulation, developed for the treatment of the 
signs and symptoms of DED 
 
 
It is a single component product consisting of 100% perfluorohexyloctane. NOV03 
addresses DED associated with MGD via a new physicochemical mode of action. Due to 
its low surface tension it rapidly spreads across the ocular surface and interacts with the 
lipophilic part of the tear film forming a layer at the tear film air interface. Such a layer 
prevents excessive evaporation of the aqueous tear film component. 
 
 
. As a water-free, single component product, it is free 
of excipients like oils, surfactants and preservatives. Related advantages include convenient 
handling, improved tolerability, and a decrease in the visual disturbance upon instillations. 
Due to this mode of action subjects with DED associated with MGD were considered to 
experience the greatest benefit from the treatment. This is in line with experience from the 




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2.4 Summary of Known and Potential Risks and Benefits to Human Subjects  
The active and only ingredient of NOV03, perfluorohexyloctane, is a semifluorinated 
alkane with a well-established tolerability and safety profile. 
 
 
 
 
 
 
 
 
It is not yet approved in the US.  
 
Safety data from the NVU-002 trial showed an excellent clinical safety and tolerability 
profile. No remarkable imbalance in terms of treatment emergent adverse events (TEAEs) 
across treatment groups were revealed. Incidence of ocular AEs was low, ranging from 
4.5% to 11.7%, and the great majority were of mild intensity. Instillation site reactions were 
reported in single cases in 3 (2.6%) subjects in NOV03 QID, 1 (0.9%) subject in NOV03 
BID and 2 (1.8%) subjects in the saline group. A total of 4 serious adverse events (SAEs) 
were reported in 4 subjects. Three (3) subjects were randomized to the NOV03 QID group 
and 1 subject was randomized to the NOV03 BID group. All SAEs were non-ocular and 
not related to trial treatment. All SAEs resolved. 
 
Slit-lamp biomicroscopy, dilated fundoscopy, mean best corrected visual acuity (BCVA) 
and intraocular pressure (IOP) observations did not indicate any treatment-related changes. 
There were no clinically significant changes in vital signs, laboratory parameters or other 
observations related to safety. 
 
Up to now four AEs of blurred vision have been reported, two were assessed as not related 
and two as related. If any visual disturbances should occur upon instillation of the drop the 
subject is advised not to drive or use machines until such effects have disappeared. 
 
 
 
 
 
 
 
 
 
 
As described in Section 2.3 the NVU-002 trial demonstrated a favorable efficacy in 
reducing signs and symptoms of DED in subjects with evaporative forms of DED
 
. This efficacy profile is supported by experience from the Post Market Clinical 
Follow-up studies. 
In summary, based on the preclinical and clinical data obtained to date, risks to subjects in 
the planned NVU-003 trial are considered very low. Furthermore, the subjects randomized 
in this trial will be closely monitored, and current standard ophthalmological safety 
assessments will be performed during the entire treatment period.  


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The efficacy demonstrated to date shows that NOV03 reduces DED signs as well as DED 
symptoms stronger than the saline comparator in the target population of subjects with DED 
  
NOV03 therefore provides a favorable benefit-risk treatment profile to subjects with DED 
 The study 904 trial is designed to replicate the results of the NVU-
003 study and confirm the positive benefit-risk profile. 
 
3 TRIAL OBJECTIVES 
3.1 Primary Objective 
• The primary objective of this trial is to assess the efficacy of NOV03 
(perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in comparison 
to a saline control for the treatment of the signs and symptoms of Dry Eye Disease 
associated with MGD. 
 
3.2 Secondary Objectives 
• The secondary objective of this trial is to assess the safety and tolerability of NOV03 
(perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in comparison 
to a saline control in subjects with Dry Eye Disease associated with MGD. 
 
• Further objectives of this trial are to explore the effect on other efficacy endpoints of 
NOV03 (perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in 
comparison to a saline control in subjects with Dry Eye Disease associated with 
MGD. 
 
4 TRIAL DESIGN 
4.1 Overall Trial Design 
This trial is a phase 3, multi-center, randomized, double-masked, saline-controlled trial to 
evaluate the effect of NOV03 (100% perfluorohexyloctane) at a QID dosing regimen on 
signs and symptoms of Dry Eye Disease. Approximately 560 male and female subjects (280 
each arm) of at least 18 years of age with a subject-reported history of DED in both eyes 
and who meet all other trial eligibility criteria will be randomized, stratified by clinical site 
and dryness score <70 vs ≥ 70 (VAS) at baseline, 1:1 to receive 1 of 2 treatments: 
Treatment 1: NOV03 (100% perfluorohexyloctane), 4 times daily (QID) 
Treatment 2: Saline (0.6% sodium chloride solution), QID 


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Each treatment group will be comprised of 280 subjects such that approximately 250 
evaluable subjects per arm complete the trial. Approximately 35 clinical sites are 
anticipated to participate. 
 
This trial will consist of two periods: Up to 14-day screening period and a 57-day treatment 
period (See Appendix 1).  
 
4.2 End of Trial Definition  
The end of the trial for an individual subject is defined as that subject’s last clinic visit or 
the date of early termination, if applicable. For subjects that are lost to follow-up, the date 
of early termination will be the date of the last attended clinic visit. The end of the trial for 
the overall trial is defined as completion of the last visit or procedure as specified in 
schedule of assessments for all subjects in the trial. 
 
4.3 Visit Description  
Subjects will be required to sign an Informed Consent before completing any trial related 
procedures. All trial procedures are listed in Section 8.4 and in the schedule of assessments 
(see Appendix 1). The ocular symptoms assessments and evaluations must be performed in 
the respective order as listed. IMP Dispensation is described in Section 7.1.4. 
 
Subjects will be instructed not to show or discuss the properties of the assigned IMP and/or 
their experience with the IMP with other trial participants, and not to show or discuss the 
IMP with the Investigator or site staff other than the dedicated dosing coordinator, unless 
instructed to do so. 
 
Screening (Visit 0) 
 
All assessments required for the screening visit must be done within 14 days before the 
randomization, baseline Visit 1. At least one eye must qualify with all of the following 
objective measures: Tear film break up time ≤5 sec, Schirmer’s Test ≥5 mm, Meibomian 
gland dysfunction (MGD) defined as MGD score ≥ 3, and total Corneal Fluorescein 
Staining (CFS) of 4≤x≤11. Subjects who fail to qualify for the trial at screening may be 
rescreened as described in Section 5.5. 
Baseline Day 1 (Visit 1) 
On Day 1 (Visit 1), eligible subjects will be evaluated for baseline signs and symptoms of 
dry eye disease and will be randomized to NOV03 QID or saline solution QID. Subjects 
will be given a 14-day supply and will self-administer a single drop of the first initial trial 
medication into each eye at the clinic. Subsequently the subject will be asked to complete 
an instillation comfort questionnaire. Each subject will be given a dosing diary to record 


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dosing. Study staff will help the subject to understand how to use the dosing diary and when 
the remaining doses should be taken. 
Visits 2-4 / (ET) 
Subjects will return to the clinic on Day 15±1 (Visit 2), 29±2 (Visit 3), and 57±2 (Visit 
4/Early Termination (ET)) to be evaluated for signs and symptoms of dry eye disease. The 
subject will be asked to complete an eyedrop acceptability questionnaire during Visit 4. 
Collection and review of IMP will be performed (used and unused trial medication should 
be returned to the clinic) and new trial medication will be dispensed at Visit 2 and Visit 3. 
The dosing diary will be collected at the clinic during each visit and checked for 
compliance. Subjects will be discharged from the trial after all Visit 4/ET assessments have 
been completed. 
Early Termination 
Subjects who terminate early during the treatment period will be asked to complete all 
assessments as indicated at Visit 4 on the schedule of assessments prior to commencement 
of any alternative dry eye therapy (if considered possible). Subjects who are terminated 
early from the trial will not be replaced. 
Trial Flow  
All subjects will be expected to progress from screening through trial exit. All subjects will 
follow the trial structure as shown in Figure 1. 
 
 
 
Figure 1 
Study 904 Flow Chart 
 
4.4 Enrollment and Treatment Assignment  
All treatment groups will be enrolled in parallel. Each subject will be assigned a unique 
subject number. All subject numbers will be assigned by Interactive Response System (IRS) 
in strict numerical sequence and no numbers will be skipped or omitted. If all eligibility 
criteria are met at Visits 0 and 1, each qualifying subject will then be randomized.  


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Site and Dryness Score <70 vs ≥ 70 (VAS) at baseline (Visit 1) are used as a stratification 
factor in this trial. IRS will be used to account for the stratification factors while assigning 
the drug kit numbers at visits 1, 2 and 3. The subjects, investigators, Clinical Research 
Organization (CRO) personnel involved in conduct and monitoring of the trial and sponsor 
will be masked to IMP assignment. 
Each subject will participate in the trial for approximately 10 weeks. The total duration of 
the trial from First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV) is 
expected to be approximately 7 months. 
 
4.5 Justification of Trial Design 
This trial is designed as a confirmatory trial to the previously conducted phase 2 trial NVU-
002 and a supportive trial to the ongoing phase 3 trial NVU-003 in subjects with DED 
associated with MGD. This population is considered to respond best based on the mode of 
action and clinical data. 
 
The trial will be a randomized, double-masked, saline controlled trial to demonstrate 
efficacy and safety of NOV03 after a 2-month treatment duration. Vehicle controlled trials 
are currently the standard for DED trials, however, as NOV03 is a 100% single component 
product, saline solution has been selected as comparator given that this most likely best 
reflects a placebo treatment. Randomization and double masking are state of the art 
measures to reduce bias. Fast onset of efficacy is important for subjects and their 
compliance to therapies, thus early demonstration of efficacy (e.g. at 2 month) is desired 
and highly clinically relevant. Moreover, DED is a fluctuating condition with recurring dry 
eye complaints that may be linked to seasonal and/ or environmental changes (Van Setten 
et al., 2016), thus a primary endpoint assessment following a shorter treatment duration is 
considered clinically relevant and has a greater potential to capture the true drug effect. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The two primary endpoints, tCFS and Dryness Score, will be tested in a hierarchical order 
with total corneal fluorescein staining being tested first as the NVU-002 data for this 
endpoint is stronger. The hierarchical testing has been selected to protect the α – error.  
 
4.6 Justification of Dose  
The NOV03 QID dosing regimen to be evaluated in this trial is based on the results from 
the phase 2 NVU-002 trial. The QID regimen showed more pronounced reductions in tCFS 
and symptom scores as measured by OSDI and VAS. This was confirmed by responder 
analyses on signs (tCFS) as well as symptoms (Dryness Score) that underlined the relevance 
of these observed changes.  
 
Based on the safety and tolerability profile seen for both treatment regimens in NVU-002 
and the consistent trend for better efficacy in NOV03 QID in both signs and symptoms the 
QID dose regimen will be tested in this trial. The aim of the current trial study 904 is to 
replicate the efficacy and safety results of NVU-002 and to provide additional supportive 
data in addition to the phase 3 trial NVU-003. 
 
5 TRIAL POPULATION 
5.1 Number of Subjects (approximate) 
An estimated 760 subjects will be screened to randomly assign at least 560 subjects to 
IMP such that approximately 250 evaluable subjects per treatment arm complete the trial. 
 
5.2 Trial population characteristics 
All subjects must be at least 18 years of age, of either gender and any race. Subjects must 
have a reported history of dry eye in both eyes and meet all inclusion criteria and none of 
the exclusion criteria. 
 
5.3 Inclusion Criteria 
Subjects will be eligible to participate in this trial if they meet all following criteria:  
1. Be at least 18 years of age at the time of consent. 
2. Provide written informed consent. 
3. Have a subject reported history of Dry Eye Disease in both eyes for at least 6 months 
prior to Visit 0. 
4. Have Tear film break-up time (TFBUT) ≤5 sec at Visit 0 and Visit 1. 
5. Have Ocular Surface Disease Index (OSDI©) ≥25 at Visit 0 and Visit 1. 
6. Have an unanesthetized Schirmer’s Test I ≥5 mm at Visit 0 and Visit 1. 
7. 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 


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from 0-3; 0 = normal, 1 = thick/yellow, whitish, particulate 2 = paste; 3 = 
none/occluded; total score will range from 0-15) at Visit 0 and Visit 1. 
8. Have a total corneal fluorescein staining score of 4≤ X ≤11 (i.e. sum of inferior, 
superior, central, nasal, and temporal) according to the National Eye Institute (NEI) 
scale at Visit 0 and Visit 1.   
9. Have at least one eye (the same eye) satisfy all criteria for 4, 6, 7, and 8 above at Visit 
0 and Visit 1. 
10. Be able and willing to follow instructions, including participation in all trial 
assessments and visits. 
 
5.4 Exclusion Criteria 
Subjects will not be eligible to participate in this trial if any of the following criteria apply: 
1. Have been randomized in NVU-002, NVU-003 or participated in the NVU-004 OLE 
Study. 
2. Have any clinically significant ocular surface slit-lamp findings at Visit 0 and Visit 1 
and/or in the opinion of the investigator have any findings that may interfere with trial 
parameters and may include eye trauma, history of eye trauma or anterior membrane 
dystrophy. 
3. Have a history of Stevens Johnson Syndrome. 
4. Have active blepharitis or lid margin inflammation that required any topical antibiotics 
or topical steroids within last 30 days prior to Visit 0 or will require such treatment 
during the trial. Any other lid margin therapy such as lid scrubs, lid wipes, warm 
compresses, systemic antibiotics (such as tetracyclines) and oral supplements for 
treatment of ocular conditions or oral supplements had to be stable within the last 30 
days prior to Visit 1 and should be maintained stable throughout the trial.  
5. Have had a LipiFlow procedure, Intense Pulse Light (IPL) procedure or any kind of 
other procedures affecting meibomian glands within 6 months prior to Visit 1. 
6. Have abnormal lid anatomy that causes incomplete eyelid closure including entropion 
and ectropion or floppy lid syndrome that exposes parts of the conjunctiva or impairs 
the blinking function of the eye (e.g. Botox injections for blepharospasm). 
7. Have received or removed a permanent punctum plug within 3 months (6 months for 
dissolvable punctum plugs) prior to Visit 1 or expected to receive a punctum plug or 
removal of a punctum plug, or a punctum plug expected to be dissolved during the trial.  
8. Have Dry Eye Disease secondary to scarring, irradiation, alkali burns, cicatricial 
pemphigoid, or destruction of conjunctival goblet cells (as with vitamin A deficiency). 
9. Have an ocular or periocular malignancy. 
10. Have a corneal epithelial defect; have significant confluent staining or filaments 
anywhere on the cornea.  
11. Have a history of herpetic keratitis. 
12. Have active ocular allergies or ocular allergies that are expected to be active during the 
trial period. 
13. Be diagnosed with an active ocular or systemic infection (bacterial, viral, or fungal), 
including fever requiring treatment with antibiotics. 


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14. Have worn contact lenses within 1 month of Visit 0 or anticipate using contact lenses 
during the trial. 
15. Have used any eye drops and/or TrueTearTM device (Intranasal Tear Neurostimulator) 
within 24 hours before Visit 1. 
16. Have had intra-ocular surgery or ocular laser surgery within the previous 6 months or 
have any planned ocular and/or lid surgeries over the trial period. 
17. Be a family member living in the same household of another randomized study 904 or 
NVU-003 subject, or a family member living in the same household of another NVU-
004 OLE participant. 
18. Be a clinical site employee that is directly involved in the management, administration, 
or support of this trial or be an immediate family member of the same.  
19. Be a woman who is pregnant, nursing or planning a pregnancy. 
20. Be unwilling to submit to a urine pregnancy test at Visit 0, Visit 1 and Visit 4 (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 bilateral tubal 
ligation or bilateral oophorectomy) or is post-menopausal (without menses for 12 
consecutive months). 
21. 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 (IUD); 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 trial, she must agree to use adequate birth control as defined above for the 
remainder of the trial. 
22. Have an uncontrolled systemic disease in the opinion of the investigator. 
23. Have a known allergy and/or sensitivity to the investigational drug or saline 
components.  
24. Have active ocular or periocular rosacea that in the judgement of the investigator 
interferes with the trial (e.g., clinically relevant lid induration). 
25. Have pterygium in any eye. 
26. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 60 days of Visit 1. 
27. Have used any topical ocular steroids treatments, topical cyclosporine, lifitegrast, 
serum tears or topical anti-glaucoma medication within 60 days prior to Visit 0. 
28. Have 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 0 or 
expected to be unstable during the trial. 
29. Have a corrected visual acuity worse than or equal to logarithm of the minimum angle 
of resolution (logMAR), +0.7 as assessed by Early Treatment of Diabetic Retinopathy 
Study (ETDRS) scale in both eyes at Visit 0 and Visit 1.  
30. Have a condition or be in a situation (including language barrier) which the investigator 
feels may put the subject at significant risk, may confound the trial results, or may 
interfere significantly with the subject’s participation in the trial. 
31. Have a history of isotretinoin (e.g. Accutane, Myorisan, Claravis, Amnesteem) use. 
 


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5.5 Re-Screen Procedures  
If the subject does not qualify at Visit 0 or Visit 1, he or she may be re-screened once after 
14 days from the relevant visit provided that new informed consent is signed, new subject 
number is received via IRS and all the assessments are repeated as per protocol 
requirements. 
 
5.6 Subject/Trial Withdrawal Criteria  
Subjects are free to discontinue their participation in the trial at any time without giving 
their reasons. 
A subject must be discontinued after randomization from the trial for any of the 
following reasons:  
• Occurrence of pregnancy; 
• Withdrawal of subject`s consent; 
• Emergency unblinding has occurred. 
A subject must be discontinued from treatment after randomization for any of the 
following reasons (but may remain in the trial for follow up assessments): 
• If at any time during the trial the investigator determines that a subject’s safety has 
been compromised; 
• Occurrence of an exclusion criterion that is clinically relevant and affects the 
subject’s safety;  
• If discontinuation is considered necessary by the investigator and/or sponsor; 
• Occurrence of Adverse Events (AEs) that present an unacceptable consequence or 
risk to the subject in the judgment of the investigator, sponsor, or the medical 
monitor; or is intolerable to the subject.  
 
If a subject has failed to attend scheduled trial assessments, the investigator must determine 
the reasons and the circumstances as completely and accurately as possible. 
In case a subject has to be withdrawn from the trial for safety reasons related to study drug, 
the sponsor will be informed immediately. If there is a medical reason for withdrawal, the 
subject will remain under the supervision of the investigator until satisfactory health has 
returned or the subject´s health has reached a stable condition.  
Subjects who are withdrawn from the trial after dosing will not be replaced.  
In case of premature withdrawal from the trial, the process outlined in Section 8.4.2 should 
be followed. In any case, the appropriate electronic Case Report Form (eCRF) section 
including the reason for discontinuation as defined in Section 8.6.2 must be completed. 


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The trial can be prematurely discontinued as described in Section 8.7. 
6 TRIAL PARAMETERS 
6.1 Efficacy Endpoints 
6.1.1 Primary Efficacy Endpoints: 
Two primary endpoints will be tested in the following order using hierarchical fixed 
sequence testing: 
 
1. Change from baseline (CFB) in total Corneal Fluorescein Staining (tCFS) (NEI scale) 
at Day 57 
2. CFB of Dryness Score (visual analogue scale [VAS] Severity of Dryness) at Day 57 
 
6.1.2 Secondary Efficacy Endpoints: 
The following secondary efficacy endpoints will be evaluated in the following order using 
hierarchical fixed sequence testing: 
 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
 
6.1.3 Other Pre-specified Efficacy Endpoints: 
1. CFB of Dryness Score (VAS) at Day 29  
2. CFB in tCFS at Day 29  
3. CFB in CFS central and inferior sub-regions (NEI scale) to each measured post-baseline 
visit. 
4. Proportion of tCFS responders (≥3 improvement based on NEI scale) at Day 57. 
5. Proportion of Dryness Score responders (≥30 % improvement from baseline) at Day 57. 
6. CFB in VAS burning/stinging, sticky feeling, foreign body sensation, itching, blurred 
vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye 
symptoms at each measured post-baseline visit. 
7. CFB in Ocular Surface Disease Index (OSDI©) at each measured post-baseline visit. 
 
 
 
 
 
  
 
 
 
 
 


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6.2 Safety Endpoints 
1. Ocular and non-ocular TEAEs 
2. Visual acuity 
3. Slit-Lamp biomicroscopy 
4. Intraocular pressure 
5. Dilated fundoscopy 
 
 
 
 
 
 
 
 
 
 


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7 TRIAL MATERIALS 
7.1 Investigational Medicinal Product(s) 
7.1.1 IMP(s)/ Formulation (s) 
NOV03 drug product is a thin, clear, preservative-free ophthalmic solution drop (see Table 
1). Saline eye drops preserved with benzalkonium chloride will be supplied as the control 
product (see Table 2). Investigational drug and control will be provided in identical bottles 
and labels to ensure the double-masked character of the trial. 
 
Table 1 
Active Investigational Product 
 
Investigational Product 
Product code: 
NOV03 
Chemical name: 
Perfluorohexyloctane  
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 
 
 
 
Table 2 
Control Investigational Product 
 
Control Investigational Product 
Product name: 
Saline solution 
Chemical name: 
Sodium chloride solution (0.6 %) 
Molecular formula: 
NaCl 
Dosage form: 
3 mL ophthalmic solution 
Unit dose: 
35-40 µL drop size 
Route of administration: 
Topical ocular administration 
Physical description: 
Colorless and clear ophthalmic solution 
Excipients: 
0.01% benzalkonium chloride w/v 
 
 
 
 
7.1.2 Labeling and Packaging of IMP 
IMP will be labelled according to the legal requirements and packaged into individual 
subject kits, each containing 2 bottles of NOV03 or saline solution. See Section 7.1.4 for 
details regarding dispensation to subjects. 


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In compliance with the Code of Federal Regulations 21 part 312, section 312.6, the labels 
for the IMP shall be comprised of: 
 
• Protocol number 
• Kit Number 
• Investigational new drug statement 
• Storage conditions 
• Name and address of the sponsor 
 
7.1.3 IMP Storage 
The IMPs must be stored in a secure area accessible only to the investigator or pharmacist 
and his/her designees. IMPs must be stored at room temperature under temperature-
monitored conditions and must not be refrigerated. Subjects should be instructed to store 
IMP at room temperature and out of children’s reach at home. Subjects should not use a 
dispensed bottle that has been opened for more than 30 days.  
 
7.1.4 IMP Dispensation 
• The dedicated dosing coordinator is responsible for dispensing the IMP and 
supervision of first dose administration at Visit 1. 
• The IMPs must only be distributed to subjects properly qualified under this protocol to 
receive IMP. 
• IMP will be provided to the clinical sites as subject kits containing 2 bottles of NOV03 
or saline solution. 
• At the end of Visit 1, qualified subjects will be randomized and a kit of IMP containing 
2 bottles for each subject will be assigned using IRS. The first dose of IMP will be 
administered at the clinical site.  
• At Visits 1 and 2 the subject will receive one subject kit.  
• At Visit 3 the subject will receive two subject kits. 
• At Visits 2, 3 and 4 used/unused IMP will be collected from subjects for drug 
accountability by the dedicated dosing coordinator.  
Subjects will be instructed to immediately contact the site if there is any problem with the 
IMP, e.g. kit/bottle(s) was damaged or lost or if the open bottle was dropped. In case the 
subject needs a replacement bottle of IMP, the next bottle from the kit can be used by the 
subject. If no bottle remains in the kit, a new kit will be assigned to the subject using IRS.  
 
7.1.5 Instructions for Use and Administration 
At Visit 1 subjects will be instructed by the dedicated dosing coordinator on appropriate 
hygiene and eye drop dosing technique. Subjects will self-administer NOV03 or saline eye 


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drops in each lower cul-de-sac of each eye as shown in Appendix 2 under the supervision 
of the dedicated dosing coordinator on Day 1 (Visit 1).  
 
Subsequent eye drops on Day 1 are to be instilled by the subjects according to detailed 
written instructions. Subjects will be instructed to instill their drops into both eyes QID for 
the duration of the trial. Clinic staff will coach the subjects to dose themselves at 
approximately the same time every day e.g., morning, lunch time/mid-day, afternoon/early 
evening, and at bedtime. If a dose is missed, then the next dose should be administered on 
time. 
The dedicated dosing coordinator will inform subjects on how to store IMP (see Section 
7.1.3) and dose IMP and how to complete their dosing diary. 
 
Dosing should be continued until the day of the next Visit (should be at least 2 hours before 
first ophthalmic examination).  
 
The bottles are designed for multiple use. Subjects will be instructed to only open one bottle 
at a time. They should be instructed not to discard the empty bottles but keep them in the 
kit box and return them at their next visit in the kit box. Subjects will record dosing in their 
dosing diary. Subjects will be instructed not to show the assigned IMP to the Investigator 
or site staff other than the dedicated dosing coordinator, unless instructed to do so. 
 
7.2 IMP Accountability 
The dedicated dosing coordinator at each site must keep an accurate accounting of IMPs 
received from the supplier by maintaining a detailed inventory. IMP shipment records will 
be verified and accountability performed by comparing the IMP shipment inventory sheet 
to the actual quantity of used/unused IMP bottles received at the site.  
 
Accurate records of receipt and disposition of the IMP (e.g. dates, quantity, subject number, 
kits used, kits unused, etc.) must be maintained by the dedicated dosing coordinator at each 
site. This includes the amount dispensed to subjects, amount returned to the site by the 
subjects, and the amount returned to the sponsor or designee upon completion of the trial.  
 
Investigational trial medication orders, records of receipts, dispensing records, and 
inventory forms will be examined and reconciled by the dedicated dosing coordinator. At 
each visit, subjects will return all bottles to clinic staff for accountability purposes. 
Accountability will be ascertained by performing reconciliation between the amount of IMP 
cartons (kits and their components) sent to the site, the amount used and unused at the time 
of reconciliation. All investigational trial medication that is dispensed during the course of 
the trial must be accounted for on an IMP accountability form. No IMP kits or bottles will 
be returned to the sponsor prior to full accountability by sponsor’s monitor. 


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7.3 IMP Handling and Return  
Unless otherwise directed, at the end of the trial all returned (used and unused) IMP must 
be directly shipped from the clinical site to the sponsor for destruction of the medications. 
Note: The medications should not be disposed or returned prior to full accountability 
by the sponsor’s monitor. The clinical site will include a copy of all completed drug 
disposition forms with the IMP to the sponsor after full accountability is completed. 
 
7.4 IMP Masking  
Investigational drug and control will be provided in identical bottles and labels to ensure 
the double-masked character of the trial. The Investigator/site staff and Bausch & Lomb, 
Incorporated. personnel or designee(s) involved in the conduct of the trial will be masked 
to the IMP. Clinical Trial Material Supply Chain are unmasked designee. 
 
Due to physicochemical differences between NOV03 and saline, there will be a dedicated 
dosing coordinator who will be responsible for the handling of IMP and activities (such as 
dispensation, collection, accountability) surrounding the use of IMP.  
 
Each site must have a dedicated dosing coordinator that will be responsible for: 
• all IMP dispensation and accountability,  
• daily diary dosing education/review,  
• all discussions with study subjects related to IMP,  
• the administration of the Eyedrop Acceptability and Instillation Comfort 
Questionnaires.  
 
This designee shall not participate in any other trial procedures and not report this 
information to other staff. Subjects will be instructed to administer the IMP out of the sight 
of the Investigator or site staff other than the dedicated dosing coordinator. Subjects are not 
to show or discuss the properties of the assigned IMP to the Investigator or site staff other 
than the dedicated dosing coordinator, unless instructed to do so. 
 
7.5 Other Trial Supplies 
Diaries, Questionnaires, Urine Pregnancy Tests, Meibomian Gland Evaluator stick, 
Schirmer’s test strips, sodium fluorescein, will be provided to sites. Respective instructions 
are available in Appendix 3 and manual of operations. 


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8 TRIAL METHODS AND PROCEDURES 
8.1 Concurrent Medications and 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 or previous medications are to be recorded for 60 days 
prior to Visit 0. Any physical therapies, or surgeries are to be documented for 6 months 
prior to Visit 0. 
Therapy considered necessary for the subject’s welfare that will not interfere with the 
evaluation of the study medication may be given at the discretion of the Investigator and in 
consultation with the medical monitor. If there is any question as to whether the medication 
may interfere, the investigator should contact the medical monitor or sponsor. Whenever 
possible, medications should be administered in dosages that remain constant throughout 
the study duration. 
Physical therapies such as lid scrubs, lid wipes, warm compresses, systemic antibiotics 
(such as tetracyclines) and oral supplements for treatment of ocular conditions must be 
stable within the last 30 days prior to Visit 1 and should be maintained stable throughout 
the trial. Changes in those therapies or initiation of such therapies should be recorded on 
the subject’s source document and corresponding eCRF. 
8.2 Prohibited Medications 
Disallowed medications and treatments are listed in the exclusion criteria (Section 5.4). All 
medications and treatments that were not allowed prior to trial are also not allowed during 
the trial in particular wearing of contact lenses, ocular surgery/ocular laser treatment of any 
kind, and no other dry eye treatments such as artificial tears, gels, or ointments or 
TrueTearTM device (Intranasal Tear Neurostimulator) shall be used within 24 hours prior to 
Visit 1 and throughout the course of the trial.  
 
Specific prohibitions: 
• Topical ocular steroid treatments, topical cyclosporine, lifitegrast, serum tears or 
topical anti-glaucoma medication within 60 days prior to Visit 0 and during the trial. 
• Oral medications known to cause ocular drying (e.g., antihistamines, 
antidepressants, etc.) on a non-stable regimen within 1 month prior to Visit 0 or 
expected to be unstable during the trial. Amitriptyline (e.g., Elavil) is only allowed 
as sleep aid and should not be used within 24 hours prior to any visit (see Section 
8.1). 
• History of isotretinoin use  
 
Concurrent enrollment in another investigational drug or medical device trial is not 
permitted. 


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8.4 Examination Procedures 
8.4.1 Procedures to be performed at each trial visit with regard to trial objective(s) 
See Appendix 1 for a schedule of visits and measurements in recommended order. 
Appendix 3 describes the eye examinations. These should not be done earlier than 2 hours 
after IMP instillation. If possible the same investigator/coordinator should perform the 
assessments for an individual subject. Primary endpoint assessments at Baseline Visit 1 
(Day 1) and Visit 4 (Day 57) should be done preferably on the same time of the day. 
The dedicated dosing coordinator will perform tasks as described in Section 7.4. 
 
Visit 0 (Up to 14 days before Visit 1): Screening 
• Informed consent / HIPAA; 
• Demographic data and medical / medication history; 
• Review of inclusion / exclusion criteria;  
• Urine pregnancy test; 
• 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 start of 
Schirmer`s test);  
• Schirmer’s test I (without anesthesia); 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Non-leading AE questioning (Adverse event query); 
• Qualified subjects will be scheduled for Visit 1. 


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Visit 1 (Day 1): Baseline/Randomization 
• Previous/Concomitant Medication; 
• Review of inclusion / exclusion criteria; 
• Urine pregnancy test; 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of 
dry eye symptoms; 
• 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 before start of 
Schirmer`s test); 
• Schirmer’s test I (without anesthesia); 
• Randomization; 
• In-office dose of IMP; 
• Instillation comfort questionnaire; 
• Non-leading AE questioning (Adverse event query); 
• Dispensation of dosing diary; 
• Drug dispensation of one kit for self-administered dosing until Visit 2; 
o Subjects will be instructed on how to administer IMP; 
o Subjects will be instructed to dose with IMP on the day of their next visit at 
least 2 hours before the start of their visit (Visit 2); 
o Subjects will be instructed on how to complete the dosing diary. 
 
Visit 2 (Day 15 ± 1), Visit 3 (Day 29 ± 2):  
• At the beginning of the visit the subject will be asked about the time of last dose. 
Assessments should be performed at least 2 hours after last dose of IMP; 
• Collection and review of IMP and dosing diary; 
o Calculate subject compliance with doses in the subject diary as described 
in Section 8.5 and re-educate subject as necessary.  
• Concomitant medication update; 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of 
dry eye symptoms; 
• Ocular Surface Disease Index (OSDI©) questionnaire;  
• Visual acuity (ETDRS); 
• Slit-Lamp biomicroscopy; 
• Fluorescein staining (NEI scale); 
• Non-leading AE questioning (Adverse event query); 
• Re-dispensation of dosing diary;  


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Visit 2 Drug dispensation of one kit for self-administered dosing until Visit 3; 
o Subjects will be instructed on how to administer IMP; 
o Subjects will be instructed to dose with IMP on the day of their next visit 
at least 2 hours before the start of their visit (Visit 3); 
o Subjects will be instructed on how to complete the dosing diary. 
Visit 3 Drug dispensation of two kits for self-administered dosing until Visit 4; 
o Subjects will be instructed on how to administer IMP; 
o Subjects will be instructed to dose with IMP on the day of their next visit 
at least 2 hours before the start of their visit (Visit 4); 
o Subjects will be instructed on how to complete the dosing diary. 
 
Visit 4 (Day 57 ± 2) or ET: 
• At the beginning of the visit the subject will be asked about the time of last dose. 
Assessments should be performed at least 2 hours after last dose of IMP; 
• Collection and review of IMP and diary; 
• Concomitant medication update; 
• Urine pregnancy test; 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of 
dry eye symptoms; 
• Ocular Surface Disease Index (OSDI©) questionnaire; 
• Eyedrop acceptability 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 before start of 
Schirmer`s test);  
• Schirmer’s test I (without anesthesia); 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Non-leading AE questioning (Adverse event query); 
• Trial exit. 
 
8.4.2 Early Termination/Discontinuation 
The following data from subjects discontinuing before randomization (i.e. screen failures) 
will be captured in the eCRF: 
• Demographics 
• AEs / SAEs 
• Reason for discontinuation (including applicable assessment results) 
 
If a randomized subject is discontinued from the trial prior to Visit 4 (Day 57 ± 2) and not 
willing to perform all subsequent visits and assessments, then all evaluations planned for 


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Visit 4 should be performed on the day of discontinuation (early termination) or at the 
discretion of the investigator. 
Randomized and dosed subjects who discontinue treatment for any reason will be 
encouraged to undergo all subsequent trial visits and assessments. 
Data from subjects discontinuing after randomization will be captured completely in the 
eCRF including Early Termination Visit and reason for discontinuation. 
 
8.4.3 Unscheduled Visits 
An unscheduled visit may be performed during the course of the trial in order to ensure 
subject safety and/or to dispense additional IMP if necessary (i.e. damaged/lost or subject 
ran out of IMP in between visits). All procedures performed at an unscheduled visit will be 
recorded in the source documents and on the unscheduled visit eCRF pages. Any 
unscheduled visit procedure listed in the eCRF that is not performed should be indicated as 
“not done.” 
 
Evaluations that may be conducted at an unscheduled visit include: 
• Slit-Lamp biomicroscopy; 
• Visual acuity; 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Urine pregnancy test (for women of childbearing potential); 
• Assessment of AEs; 
• Assessment of concomitant medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 
 
8.5 Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of IMP at Visits 1, 2, and 3, 
and provided with written instructions (see Appendix 2). The used and unused IMP bottles 
will be collected from subjects at Visits 2, 3 and 4 to assess subject dosing compliance.  
 
Subject dosing compliance will be determined by the subject’s response or lack thereof to 
the prompt “Was the dose taken?” in the subject diary. If more than 20% of the responses 
to the total expected dose-taken prompts are checked “no,” left blank, or missing, then the 
subject will be deemed noncompliant for dosing and a deviation recorded e.g., 12 checked 
“no,” left blank, or missing at Visit 2 and Visit 3 and more than 24 at Visit 4. 
 
8.6 Subject Disposition 
8.6.1 Completed Subjects 
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8.6.2 Discontinued subjects 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to the CRO and/or trial sponsor and will be clearly documented in the eCRF as: 
• Adverse event; 
• Protocol violation; 
• Lack of efficacy; 
• Administrative reason (e.g. inability to continue, lost to follow up); 
• Sponsor termination of trial; 
• Subject choice (e.g. withdrawal of consent);  
• Other 
Subjects must be discontinued as outlined in Section 5.6. 
Subjects who discontinue for any reason after randomization will not be replaced. 
 
8.7 Trial Termination 
The whole trial may be discontinued prematurely in the event of any of the following:  
• New information leading to unfavorable risk-benefit judgment of the IMP, e.g. 
due to: 
o Occurrence of significant previously unknown adverse reactions or 
unexpectedly high intensity or incidence of known adverse reactions, or 
o Other unfavorable safety findings. 
• Sponsor’s decision that continuation of the trial is unjustifiable for medical or 
ethical reasons. 
• Poor enrollment of subjects making completion of the trial within an 
acceptable time frame unlikely. 
• Discontinuation of development of the sponsor’s IMP. 
• Terminated or suspended upon request of Health Authorities. 
 
Health Authorities and Institutional Review Boards (IRBs)/ Independent Ethics 
Committees (IECs) will be informed about the discontinuation of the trial in accordance 
with applicable regulations. 
 
8.8 Trial Duration 
An individual subject’s participation will involve 5 visits over approximately a 10-week 
period, including screening. After the trial, subjects will be treated according to standard of 
care, at the discretion of the treating physician. The total duration of the trial from “first 
subject in” to “last subject out” is expected to be 7 months. 
 


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9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related. An AE can 
therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease occurring after the subject signature of the ICF without any judgment 
on causality. 
 
If there is a worsening of a medical condition that was present prior to Visit 0, this should 
also be considered a new AE and reported. Any medical condition present prior to the 
administration of the IMP that remains unchanged or improved should not be recorded as 
an AE at subsequent visits. 
 
Worsening of DED will be considered an AE only if the dry eye status of the subject 
exceeds their previous experiences with the condition. This will be determined by the 
subject and the investigator. 
 
A clinically significant visual acuity worsening (defined as an increase of 0.22 or greater in 
logMAR score) from screening (Visit 0) will be considered an Adverse Event. 
 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IMP, expectedness, action(s) taken, seriousness, and outcome of 
any sign or symptom observed by the physician or reported by the subject upon non-leading 
AE questioning. 
 
AEs (both elicited and observed) and SAEs will be monitored throughout the trial. The 
investigator will promptly review all AEs for accuracy and completeness. All AEs will be 
documented on the appropriate source document and eCRF. 
 
Adverse events recorded from the signing of informed consent through the last study visit 
must be reported, regardless of whether or not the AEs are considered study-related. 
 
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 IMP 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. 
 


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9.1.2 Relationship to Investigational Product 
The relationship of each AE to the investigational drug should be determined by the 
investigator using these explanations: 
• Suspected: A reasonable possibility exists that the investigational product 
caused the AE.  
• Not Suspected: A reasonable possibility does not exist that the investigational 
product caused the AE.  
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the investigational product caused the AE. “Reasonable possibility” means there is 
evidence to suggest a causal relationship between the investigational product and the AE. 
Types of evidence that would suggest a causal relationship between the investigational 
product and the AE include: a single occurrence of an event that is uncommon and known 
to be strongly associated with IMP exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome); one or more occurrences of an event that is not commonly associated 
with IMP exposure, but is otherwise uncommon in the population exposed to the IMP (e.g., 
tendon rupture); an aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the trial population independent of drug therapy) that 
indicates those events occur more frequently in the IMP-treatment group than in a 
concurrent or historical control group. 
 
9.1.3 Expectedness 
The expectedness of a treatment emergent AE should be determined based upon existing 
safety information about the IMP. The active ingredient of NOV03 is perfluorohexyloctane, 
which is a semifluorinated alkane with a well-established tolerability and safety profile. It 
has been tested in four PMCF studies and one phase 2 clinical trial up to now with >370 
subjects that received NOV03 treatment. AEs of those studies have been listed in the 
Investigator’s Brochure. Therefore, the following definitions will be used: 
 
• Unexpected: An AE that is not listed in the investigator’s brochure in the Adverse 
Reaction Section at the specificity or severity that has been observed. 
• Expected: An AE that is listed in the investigator’s brochure in the Adverse 
Reaction Section at the specificity and severity that has been observed. 
• Not Applicable: Any AE with an onset prior to first dose of IMP. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the sponsor’s determination. 
 
9.1.4 Outcome 
The outcome of any AE will be determined and recorded using the following categories: 
 
• Recovered/Resolved 
• Recovering/Resolving 


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• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Lost to Follow-up 
• Fatal 
• Unknown 
 
9.2 Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator, medical monitor or 
sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
o Note:  An AE is considered “life-threatening” if, in the view of either the 
investigator, medical monitor 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; 
o Note:  The term “inpatient hospitalization” refers to any inpatient admission (even 
if less than 24 hours). For chronic or long-term inpatients, inpatient admission 
includes transfer within the hospital to an acute/intensive care inpatient unit. 
Inpatient hospitalization does not include: emergency room visits; outpatient/same-
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
o 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; 
o Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g. 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
• A congenital anomaly/birth defect; 
• Medically important 
o 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. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 


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9.3 Procedures for Reporting Serious Adverse Events 
All AEs and their outcomes must be reported to CRO, the trial sponsor, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate source document and eCRF page. 
 
9.3.1 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IMP, must be 
immediately (i.e. within a maximum 24 HOURS after becoming aware of the event) 
reported to CRO. All information relevant to the SAE must be recorded on the appropriate 
SAE report form. Within 24 hours of knowledge of a new SAE, the investigator must enter 
the SAE information onto the hard copy SAE report form and send the form to the 
 
 The investigator must verify that the report was received by 
CRO. If the investigator is not able to verify it was successfully received by CRO, the 
investigator must call the CRO clinical study manager by phone to follow-up. The CRO 
will forward the documentation to the medical monitor and the sponsor for review. 
 
The information entered must contain sufficient information to enable medical assessment 
by the medical monitor. At a minimum, the initial SAE report should contain the following 
information: 
 
● Subject’s trial ID number 
● Description of the Serious Adverse Event 
● Date of the Serious Adverse Event  
● Criterion for seriousness 
● Preliminary assignment of causality to IMP 
 
All information relevant to the SAE must be recorded on the appropriate case report forms. 
The investigator is obligated to pursue and obtain information requested by CRO, CRO 
and/or the sponsor in addition to that information reported on the case report form. All 
subjects experiencing a SAE must be followed up and the outcome must be reported. 
The investigator must 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 CRO and the trial 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 IMP; and inform the IRB of the AE within their guidelines for reporting 
SAEs. 
 
All SAEs will be reported from the signature of Informed Consent until 30 days after the 
last administration of study drug. 
 
All SAEs will be followed until resolution, stabilization, the event is otherwise, explained, 
or the subject is lost to follow-up. 
 


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Investigators are not obligated to actively seek SAE information from subjects that 
completed the study, but investigators are encouraged to notify the Sponsor, or designee, 
of any SAEs of which they become aware occurring at any time after a subject has 
discontinued or completed the study that they judge may be reasonably related to treatment 
with study drug. 
 
9.3.2 Reporting a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
All SAEs that are ‘suspected’ and ‘unexpected’ are to be reported to CRO within 24 hours 
after the site becomes aware of the event, via the SAE reporting process outlined above. All 
SAE/SUSARs will be promptly reported to the IRB/IEC and governing health authorities 
(e.g., United States Food and Drug Administration [FDA]) as required by the IRB/IEC, 
federal, state, and local regulations and timelines. 
 
9.4 Procedures for Unmasking of IMP 
All subjects, investigators, and trial personnel involved with the conduct of the trial will be 
masked with regard to treatment assignments. The mask may be broken in exceptional 
circumstances.  
In a medical emergency, when the management of a subject’s condition requires knowledge 
of the treatment assignment, the investigator, or designee, will obtain the trial treatment 
assignment from the Interactive Response System (IRS). If possible, the medical 
emergency should be discussed with the medical monitor prior to obtaining the treatment 
assignment, or as soon after as possible. The sponsor may unmask for regulatory submission 
determination of an SAE when necessary (see Section 9.3.1). 
In a non-emergency situation, when a code break is required, it must be discussed with the 
medical monitor and/or CRO and the trial sponsor. The code break must be approved in 
writing by the sponsor. 
If the randomization code for a subject is broken, the investigator will record the date and 
reason for lifting the mask for that subject in the source documents. Upon unmasking, the 
subject will be withdrawn from the trial and should complete both the Early Termination 
and Follow-up procedures. 
 
9.5 Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to follow-
up or until the AE is otherwise classified. Resolution means the subject has returned to 
baseline state of health or the investigator does not expect any further improvement or 
worsening of the AE. If the subject is lost to follow-up, the investigator should make 3 
reasonable attempts to contact the subject via telephone, post, or certified mail. All follow-
up will be documented in the subject’s source document. Non-serious AEs identified on the 
last scheduled contact must be recorded on the AE eCRF with the status noted.  
 


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If the investigator becomes aware of any new information regarding an existing SAE (i.e. 
resolution, change in condition, or new treatment), a new SAE Report Form must be 
completed and faxed to CRO within 24 hours of the site’s awareness of the new 
information. The original SAE form is not to be altered, but a new SAE Report Form must 
be completed and identified consecutively based on the previous report form (i.e. Initial 
Report, Follow-up #1, Follow-up #2, etc.). The report must describe whether the event has 
resolved or continues and how the event was treated. 
 
9.6 Reporting Pregnancies 
Pregnancy itself is not considered an AE or SAE (unless there is a suspicion that the IMP 
may have interfered with the effectiveness of a contraceptive medication). Pregnancy is an 
important medical event that must be followed up. Any pregnancy that occurs during the 
clinical trial where the fetus could have been exposed to IMP must be followed through the 
outcome of the pregnancy.  
 
It is the responsibility of the Investigator to obtain the outcome and condition of the infant 
information within 30 calendar days after the initial notification and approximately 30 
calendar days postpartum. 
 
If a subject or investigator suspects that the subject may be pregnant prior to IMP 
administration, the IMP must be withheld until the results of pregnancy testing are 
available. If pregnancy is confirmed, the subject must not receive IMP and must not be 
enrolled in the trial. If pregnancy is suspected while the subject is receiving IMP treatment, 
the IMP must immediately be withheld until the result of pregnancy testing is known. 
 
If a female reports a pregnancy or has a positive pregnancy test during the trial, then the 
investigator must report the pregnancy and the outcome of the pregnancy to the CRO within 
24 hours of learning about the pregnancy and outcome of the pregnancy respectively. 
 
A Pregnancy Report Form will be completed by the trial site’s principal investigator and 
and send the form to the 
. The investigator must verify 
the report was received by CRO. If the investigator is not able to verify it was successfully 
received by CRO, the investigator must call the CRO clinical study manager by phone to 
follow-up. The CRO will forward the documentation to the medical monitor and the 
sponsor for review. 
 
At the completion of the pregnancy, the Pregnancy Report Form is to be submitted to the 
CRO via the SAE contact details.  
 
 


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10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
The following analysis populations will be considered: 
 
Full Analysis Set (FAS) – The FAS includes all randomized subjects who received at least 
one dose of investigational product. The primary analysis will be performed on the FAS. 
Subjects in the FAS will be analyzed as randomized. 
 
Per Protocol Set (PPS) – The PPS includes subjects in the FAS who do not have significant 
protocol deviations and who complete the study. Protocol deviations will be assessed prior 
to database lock and unmasking. The PPS will be analyzed using observed data only for 
efficacy variables. Subjects in the PPS will be analyzed as treated. 
 
Safety Set (SAF) – The SAF includes all randomized subjects who have received at least 
one dose of the investigational product. The SAF will be analyzed for all safety 
assessments. Subjects in the SAF will be analyzed as treated.  
 
The statistical analysis of safety data will be performed for the SAF. The analysis of 
baseline and efficacy data will be performed for the FAS. The primary efficacy analyses 
will also be performed on the PPS as sensitivity analyses. 
 
10.2 Statistical Hypotheses 
The primary endpoints will be tested in a hierarchical fixed sequence in the following order. 
 
The statistical hypotheses for the primary endpoint of CFB corneal fluorescein staining 
(NEI scale) total score at Day 57 are as follows: 
 
H01: 
The difference, between study eyes treated with NOV03 and study eyes 
treated with saline, in the mean CFB corneal fluorescein staining (NEI scale) 
total score at Day 57 = 0. 
 
HA1:  The difference, between study eyes treated with NOV03 and study eyes 
treated with saline, in the mean CFB corneal fluorescein staining (NEI scale) 
total score at Day 57 ≠ 0, with superiority claimed if the difference is less 
than 0 (NOV03 minus saline). 
 
The statistical hypotheses for the hierarchical primary endpoint of the CFB Dryness Score 
at Day 57 are as follows: 
 
H02: 
The difference, between subjects treated with NOV03 and subjects treated 
with saline, in the mean CFB Dryness Score at Day 57= 0. 
 
HA2:  The difference, between subjects treated with NOV03 and subjects treated  


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with saline, in the mean CFB Dryness Score at Day 57 ≠ 0, with superiority 
claimed if the difference is less than 0 (NOV03 minus saline). 
 
Hierarchical fixed sequence testing will be employed to maintain the type I error rate within 
the two primary endpoints. The primary analyses will first test the difference in the mean 
CFB corneal fluorescein staining (NEI scale) total score between treatments at Day 57. If 
the test of the difference is statistically significant at the two-sided alpha = 0.05 level in 
favor of NOV03 then the trial will be considered a success; NOV03 will be declared to be 
superior to saline in the mean CFB corneal fluorescein staining (NEI scale) total score at 
Day 57; and the difference in the mean CFB total Dryness Score between treatments at Day 
57 will be tested at the two-sided alpha = 0.05 level. 
 
If in addition to a statistically significant test of the difference in the mean CFB corneal 
fluorescein staining (NEI scale) total score at Day 57 is in favor of NOV03, and the test of 
the difference in the mean change from Dryness Score at Day 57 is also statistically 
significant in favor of NOV03, then NOV03 will be declared to be superior to saline in both 
the mean CFB corneal fluorescein staining (NEI scale) total score and the mean CFB of the 
Dryness Score at Day 57. 
 
10.3  Sample Size 
 
 
 
 
 
The study has been designed to have at least 95% power to reject both H01 and H02 assuming 
independence between the sign and symptom endpoint; positive correlation between these 
two endpoints would increase the overall power.  
Two hundred fifty (250) subjects (study eyes) per treatment group yields 97.9% power to 
reject H01 in favor of HA1 and conclude superiority of NOV03 over saline in the mean CFB 
tCFS score at Day 57 assuming a true difference (NOV03 minus saline) of -1.0, a common 
standard deviation of 2.8, and a two-sided alpha = 0.05. Two hundred fifty (250) subjects 
per treatment group yields 97.9% power to reject H02 in favor of HA2 and conclude 
superiority of NOV03 over saline in the mean CFB Dryness Score (VAS) at Day 57 
assuming a true difference (NOV03 minus saline) of -10, a common standard deviation of 
28, and a two-sided alpha = 0.05. Accounting for an assumed 10% subject discontinuation 
rate, approximately 560 subjects (280 subject each arm) will be randomly assigned to trial 
treatment such that approximately 250 evaluable participants per arm complete the trial. 
 


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Therefore, assuming independence between tCFS score and Dryness Score (VAS), 250 
FAS subjects per treatment group at Day 57 yields 97.9%* 97.9%= 95.8% power to reject 
both H01 and H02. 
 
10.4 Statistical Analysis 
10.4.1 General Considerations 
Quantitative variables will be summarized using number of subjects (n), mean, median, 
standard deviation, minimum and maximum. The qualitative variables will be summarized 
using counts and percentages.  
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and AEs will be 
coded to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline measures are defined as the last non-missing measure prior to the initiation of 
randomized study treatment. 
All primary and secondary analyses will be two-sided at a significance level of 0.05. 
 
10.4.2 Unit of Analysis 
For efficacy endpoints, the unit of analysis will be the study eye as defined by the following: 
Study Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria. In the case 
that both eyes are eligible for analysis, the worst eye shall be chosen, and this will be defined 
as the eye with worse (higher) total corneal staining at Visit 1. If the total corneal staining 
is the same in both eyes then the right eye will be selected as the study eye. 
 
10.4.3 Missing Data 
The primary analysis will be completed on the FAS with available data per subject, 
assuming the overall study discontinuation rate is <5%.  If the overall study 
discontinuation rate is ≥5% then the primary analysis will be based on the primary 
imputation methodology as defined Section 10.4.5 and the available data analyses will 
become robustness analyses. 
Additionally, robustness analyses will include repeating the primary analysis on the per 
protocol set (PPS); the FAS imputing missing data using last observation carried forward 
(LOCF); the FAS imputing missing data using Markov Chain Monte Carlo (MCMC) 
multiple imputation methodology under different assumptions of missingness (at random 
and not at random) each using 30 imputed values. 
 
The imputation model, for each visit, under the assumption of missing at random is: 
 
PROC MI DATA=INDATA SEED=97656 OUT=OUTDATA1 MINIMUM = 0 MAXIMUM = 3 ROUND 
= 1 NIMPUTE=30; 
  MCMC INITIAL=EM; 
  BY <TREATMENT>; 


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  VAR <BASELINE> <PARAMETER>; 
RUN; 
where PARAMETER has 5 levels and refers to the corneal fluorescein staining 
score for each region (inferior, superior, central, temporal, and nasal). 
The imputation model, for each visit, under the assumption of missing not at 
random is: 
PROC MI DATA=INDATA SEED=36797 OUT=MDATA MINIMUM = 0 MAXIMUM = 3 ROUND = 
1 NIMPUTE=30; 
  MCMC IMPUTE=MONOTONE; 
  VAR <BASELINE> <PARAMETER>; 
RUN; 
 
PROC MI DATA=MDATA SEED=38549 OUT=OUTDATA2 MINIMUM = . 0 0  
 
MAXIMUM = . 3 3 ROUND = . 1 1; 
  CLASS <TREATMENT>; 
  MONOTONE REG(<PARAMETER> = <BASELINE> / DETAILS); 
  MNAR MODEL(<PARAMETER> / MODELOBS=(<TREATMENT>=’Saline’)); 
  VAR <TREATMENT> <BASELINE> <PARAMETER>; 
RUN; 
 
where PARAMETER has 5 levels and refers to the corneal fluorescein staining score for 
each region (inferior, superior, central, temporal, and nasal). 
 
10.4.4 Multiplicity Consideration 
To control for inflation of type 1 error rate due to multiple hypotheses, the analysis of the 
two primary endpoints will be conducted in a hierarchical manner. 
 
If both primary endpoints demonstrate statistically significant superiority of NOV03 versus 
saline at the two-sided alpha = 0.05 level, the following secondary endpoints will be tested 
hierarchically to maintain an overall two-sided alpha = 0.05. 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
 
10.4.5 Primary Efficacy Analyses 
The primary comparisons in this trial will be between NOV03 versus saline at Day 57 in 
the FAS with available data per subject using the following estimands: 
• Population: Subjects with DED defined through enrollment criteria 
• Endpoint:  
o CFB in tCFS in the study eye at Day 57 
o CFB of Dryness Score (VAS) at Day 57 
• Intercurrent event:  
o Discontinuation of study medications is ignored. [treatment policy strategy] 
o Non-optimal compliance is ignored. [treatment policy strategy] 


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o Withdrawal due to any reason. Missing data not imputed. [hypothetical 
strategy] 
• Population-level summary:  
o Difference in the mean CFB in tCFS in the study eye at Day 57 between 
NOV03 and saline. 
o Difference in the mean CFB of Dryness Score (VAS) at Day 57 between 
NOV03 and saline. 
If the overall study discontinuation rate is ≥5% then the primary analysis will be based on 
imputation methodology using the following estimands and the available data analyses will 
become robustness analyses.:  
• Population: Subjects with DED defined through enrollment criteria 
• Endpoint:  
o CFB in tCFS in the study eye at Day 57 
o CFB of Dryness Score (VAS) at Day 57 
• Intercurrent event:  
o Discontinuation of study medications is ignored. [treatment policy strategy] 
o Non-optimal compliance is ignored. [treatment policy strategy] 
o Withdrawal due to lack of efficacy or adverse events. Baseline observation 
carried forward (BOCF) is used to impute missing data [hypothetical 
strategy]. 
o Missing data without withdrawal or withdrawal due to reasons other than 
lack of efficacy or adverse events. Multiple imputations using randomized 
treatment-based Markov Chain Monte Carlo is used to impute missing data 
[hypothetical strategy]. 
• Population-level summary:  
o Difference in the mean CFB in tCFS in the study eye at Day 57 between 
NOV03 and saline. 
o Difference in the mean CFB in Dryness Score (VAS) at Day 57 between 
NOV03 and saline. 
 
The primary comparison in this trial will be between NOV03 versus saline at Day 57. The 
primary efficacy endpoints (e.g. CFB in total corneal fluorescein staining [NEI scale] and 
Dryness Score) will be tested using hierarchical fixed sequence testing and summarized 
descriptively (n, mean, standard deviation, median, min, and max) and analyzed separately 
using an ANCOVA model with terms for baseline value, and treatment. 
 
Least squares mean for each treatment group and for the difference between treatment 
groups will be presented from each model together with two-sided p-values (used for 
primary inference) and 95% confidence intervals. 
 
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures analysis 
comparing treatment groups will be performed as sensitivity analyses. The mixed-effect 
repeated measures model will include treatment, baseline value, visit, and the interaction 
between treatment and visit as fixed effects, and subject as a random effect. An unstructured 


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covariance matrix will initially be used to model the covariance among repeated measures; 
however, if the model fails to converge using this covariance structure, either heterogeneous 
TOEPLITZ, homogeneous TOEPLITZ, or compound symmetry will be implemented 
according to the Akaike information criterion with a correction for finite sample sizes 
(AICc). 
 
10.4.6  Secondary Efficacy Analyses 
The following secondary endpoints will be tested hierarchically: 
 
1. CFB of Dryness Score (VAS) at Day 15. 
2. CFB in tCFS (NEI scale) at Day 15.  
3. CFB VAS burning/stinging at Day 57. 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57. 
 
Inference will only be made on these endpoints, at a 2-sided alpha = 0.05, if both primary 
endpoints and any higher order secondary endpoints are statistically significant at a 2-sided 
alpha = 0.05 in favor of NOV03. 
Quantitative secondary efficacy endpoints will be summarized similarly to the primary 
effiacy endpoints. 
The primary analysis of the secondary endpoints will use the FAS with available data per 
subject, assuming the overall study discontinuation rate is <5%. If the overall study 
discontinuation rate is ≥5%, then the primary analysis of the secondary endpoints will be 
based on imputation methodology as defined in Section 10.4.5 and the available data 
analyses will become robustness analyses. 
 
10.4.7 Other Pre-specified Efficacy Analyses 
The analyses of other pre-specified endpoints will use the Full Analysis Set (FAS) with 
available data per subject. 
 
1. CFB of Dryness Score (VAS) at Day 29. 
2. CFB in tCFS at Day 29. 
3. CFB in CFS central and inferior sub-regions (NEI scale) to each measured post-baseline 
visit. 
4. Proportion of tCFS responders (≥3 improvement based on NEI scale) at Day 57. 
5. Proportion of Dryness Score responders (≥30 % improvement from baseline) at Day 57. 
6. CFB in VAS burning/stinging, sticky feeling, foreign body sensation, itching, blurred 
vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye 
symptoms at each measured post-baseline visit. 
7. CFB in Ocular Surface Disease Index (OSDI©) at each measured post-baseline visit. 
Quantitative other pre-specified efficacy endpoints will be summarized descriptively (n, 
mean, standard deviation, median, min and max) by visit, and analyzed similarly to the 
primary endpoint at each measured visit. Least squares mean for each treatment group and 


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for the difference between treatment groups will be presented from the model together with 
two-sided p-values and 95% confidence intervals.  
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures analysis 
will also be presented as sensitivity analyses.  
Other pre-specified endpoints evaluating the proportion of study eyes (or subjects) meeting 
pre-defined criteria will be presented and tested between treatment groups using logistic 
regression analysis adjusting for baseline tCFS score at each measured follow-up visit. 
Pearson chi-squared analysis comparing the treatment groups will be performed as 
sensitivity analyses. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Exploratory and other endpoints will be summarized and analyzed similarly to the other 
pre-specified endpoints. 
 
10.4.10 Safety Variables Analyses 
All safety analyses will be performed on the Safety Population. The primary evaluation of 
safety of the active arm will be against the control arm. 
 
Extent of Exposure 
Dosing information for each treatment and each subject will be listed. Discontinuation of 
treatment will be summarized by treatment received. The primary reason for IMP 
discontinuation will also be summarized by treatment received. 
 
Analysis of Adverse Events 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and 
percentages of subjects with TEAEs, serious TEAEs, and TEAEs causing premature 
discontinuation will be provided by treatment group. An AE is treatment emergent if it 
occurs or worsens after the first dose of trial treatment. Furthermore, frequencies will be 


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given of subjects with TEAEs by system organ class; by system organ class and preferred 
term; by system organ class, preferred term and maximal severity; by system organ class, 
preferred term and strongest relationship; and by system organ class, preferred term, 
maximal severity, and strongest relationship. Separate summaries will be performed for 
ocular and non-ocular AEs.  
 
The treatment groups will be compared in regard to safety endpoints descriptively. No 
inferential comparison will be conducted. 
 
Concomitant Medications 
Concomitant medications will be coded using the most recent version of WHO-Drug 
Dictionary and summarized by treatment group. 
 
Other safety endpoints including those assessed by visual acuity, slit-lamp biomicroscopy, 
dilated fundoscopy, and intraocular pressure will be summarized by treatment group and 
visit using descriptive statistics. Changes from baseline will also be summarized where 
appropriate. For assessments performed by eye, study eye and fellow eye will be 
summarized separately.  
 
10.4.11 Interim Analyses 
No interim analyses are planned for this trial. 
 
10.5 Additional Analyses 
No further analysis is planned. 
 
10.6 Methods to Minimize Bias 
This is a randomized treatment assignment, double-masked, multi-center trial. Subjects will 
be instructed not to show or discuss the properties of the assigned Investigational Medicinal 
Product (IMP) and/or their experience with the IMP with other trial participants, and not to 
show or discuss the IMP with the Investigator or site staff other than the dedicated dosing 
coordinator, unless instructed to do so. 
 
A dedicated dosing coordinator at each site will be responsible for instructing subjects 
regarding IMP handling/administration, IMP dispensation and accountability, reviewing 
daily dosing diaries, performing the Instillation Comfort Questionnaire, the Eyedrop 
Acceptability Questionnaire and all discussions with study subjects related to IMP.  
 
 


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11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This trial will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs), including the International Conference on Harmonization (ICH) Guidelines, and 
in general, consistent with the Declaration of Helsinki. In addition, all applicable local, 
state, and federal requirements relevant to the use of IMPs in the countries involved will be 
adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent must take place before any trial specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject prior to enrollment 
into the trial. 
 
All informed consent forms must first be approved by the sponsor and receive approval 
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 
the governing IRB/IEC and that it is read, signed and dated by all subjects subsequently 
enrolled in the trial as well as those currently enrolled in the trial, as recommended by the 
the governing IRB. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This trial is to be conducted in accordance with Institutional Review Board regulations 
(U.S. 21 CFR Part 56.103). Only an IRB/IEC approved version of the informed consent 
form will be used. 
 
11.2 Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that originated with 
the Declaration of Helsinki. 
 
11.3 Subject Confidentiality 
All personal trial subject data collected and processed for the purposes of this trial 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 CRO, the sponsor, the IRB/IEC 
approving this trial, the FDA, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted direct 


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access to the trial subject’s original medical and trial records for verification of the data 
and/or clinical trial procedures. Access to this information will be permitted to the 
aforementioned individuals to the extent permitted by law. 
 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the IMP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s trial subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and EKGs. The investigator’s electronic copy of the eCRFs serves as the 
investigator’s record of a subject’s trial-related data. 
11.4.1 Retention of Documentation 
All trial related correspondence, subject records, consent forms, record of the distribution 
and use of all IMP and copies of case report forms should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region; or until at least 
two years have elapsed since the formal discontinuation of clinical development of the IMP. 
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. The investigator must notify the sponsor prior to destroying trial documentation 
even after the above-mentioned time has passed. 
 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping trial records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
 
11.5 Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs) 
All subject data will be captured in the subject source documents which will be entered  
into the eCRFs in the Electronic Data Capturing System (EDC). The investigator is 
responsible for ensuring that trial data is completely and accurately recorded in the source 
documents, data entered into each subject’s eCRF, and all trial-related materials. All trial 
data should also be attributable, legible, contemporaneous, and original. Recorded data 
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).  
 


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The EDC system is conforms to 21 CFR Part 11 requirements and data entry into the system 
will be performed only by staff that have been trained and have access to the system. An 
audit trail will be maintained within the system to capture all changes made within the 
database. After the end of the trial and database lock, copies of all applicable subjects’ 
eCRFs will be provided to each investigator site to be maintained on file by the investigator. 
 
11.6 Monitoring and Quality Assurance 
During the course of the trial a clinical research associate (CRA) will make routine site 
visits to review protocol compliance, assess IMP accountability, and ensure the trial 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 trial monitoring (including medical monitoring) will 
be outlined in a monitoring plan. 
Domestic and foreign regulatory authorities, and quality assurance, sponsor 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 with consideration to data 
protection as well as subject confidentiality to the extent that local, state, and federal laws 
apply. 
 
11.7 Handling of Biological Specimens 
Not applicable. 
 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved 
in the trial. Authorship will be established before writing the manuscript. The trial sponsor 
will have the final decision regarding authorship, manuscript and publication. 
 
 
 
 
 
 
 
 
 


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12 REFERENCES 
1. Benitez-del-Castillo J, Labetoulle M, Baudouin C, et al. (2017). Visual acuity and 
quality of life in DED: Proceedings of the OCEAN group meeting. The Ocular Surface 
15, 169-178. 
2. Craig, J. P. (2017). TFOS DEWS II Definition and Classofocation Report. The Ocular 
Surface, 15, 276-283. 
3. Le Q, Zhou X, Ge L, Wu L, Hong J, Xu J. Impact of dry eye syndrome on vision-related 
quality of life in a non-clinic-based general population. BMC Ophthalmology 2012; 
12(22): 1-8 
4. Lemp M. Report of the National Eye Institute/Industry Workshop on Clinical Trials in 
Dry Eyes. CLAO J. 1995; 21 (4): 221‐32. 
5. Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. Prevalence of dry eye among 
an elderly Chinese population in Taiwan: the Shihpai Eye Trial. Ophthalmology 2003; 
110(6):1096-101. 
6. McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The 
epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998; 105(6):1114-
9. 
7. Novack GD, Penny A, Barabino S, Bergamini MVW, Ciolino JB, Foulks GN, Goldstein 
M, Lemp MA, Schrader S, Woods C, Stapleton F. TFOS DEWS II Clinical Trial Design 
Report. The Ocular Surface 2017: 635-655. 
8. Pflugfelder SC, de Pavia CS. The pathophysiology of dry eye disease. What we know 
and future directions for research. Ophthalmology 2017; 124: S4-S13. 
9. Schaumberg DA, Sullivan DA, Dana MR. (2002). Epidemiology of dry eye syndrome. 
Adv Exp Med Biol, 506, 989-98. 
10. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. (2003). Prevalence of dry eye 
syndrome among US women. Am J Ophthalmol, 136, 318-26. 
11. Schaumberg DA, Dana R, Buring JE, Sullivan DA (2009). Prevalence of dry eye disease 
among US men: estimates from the Physician's Health Studies. Arch Ophthalmol, 127, 
763-8. 
12. Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W. Utility 
Assessment among patients with dry eye disease. Ophthalmology 2003; 110: 1412-
1419. 
13. Van Setten G, Labetoulle M, Baudouin C, Rolando M. Evidence of seasonality and 
effects of psychometry in dry eye disease. Acta Ophthalmol. 2016: 1-8. 
 
 






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5. Put the screw cap back on after administration. 
 
If a subject has difficulties with step 4 to 7 of Figure A, advise to refer to step 2 of  
Figure B: subject to squeeze bottle very gently or to wait until drop drips from the bottle 
without squeezing. 
 
 


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Appendix 4  Amendment Summary of Changes 
 
Page 
Original Text 
Amended Text (in bold) 
Rationale 
1 
Version 1.0 
Version 2.0 
New version of 
protocol 
1 
 
Amendment 1: 09 NOV 2020 
Generation of 
Amendment 1 
2 
 
 
Correction 
5, 27 
6. Have 
abnormal 
lid 
anatomy 
that 
causes 
incomplete eyelid closure 
including entropion and 
ectropion or floppy lid 
syndrome that exposes 
parts of the conjunctiva or 
impairs 
the 
blinking 
function of the eye.    
6. Have abnormal lid anatomy that 
causes incomplete eyelid closure 
including entropion and ectropion 
or floppy lid syndrome that 
exposes parts of the conjunctiva 
or impairs the blinking function of 
the eye (e.g. Botox injections for 
blepharospasm). 
Added 
clarification 
7, 28 
 
31. Have a history of isotretinoin 
(e.g. 
Accutane, 
Myorisan, 
Claravis, Amnesteem) use. 
Added 
36 
 
• History of isotretinoin use  
Added 
43 
The expectedness of an AE 
should be determined based 
upon existing safety 
information about the IMP. 
The expectedness of a treatment 
emergent AE should be determined 
based upon existing safety 
information about the IMP. 
Clarification 
43 
• Not Applicable: Any AE 
that is unrelated to the 
IMP. 
• Not Applicable: Any AE with an 
onset prior to first dose of IMP. 
 
Clarification 
73 
 
Appendix 4: Summary of Changes 
Added 
74 
 
Amendment 1 Date: 09 NOV 2020 
Generation of 
Amendment 1 
75 
 
Amendment 1 Date: 09 NOV 2020 
Generation of 
Amendment 1 
 
 




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Appendix 6  Investigator’s Signature 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Saline-Controlled Trial to Evaluate the Effect of NOV03 
(Perfluorohexyloctane) on Signs and Symptoms of Dry Eye 
Disease Associated with Meibomian Gland Dysfunction 
(Mojave Study) 
Protocol Number: 
904 
Date: 
05 AUG 2020  
Amendment 1 Date: 
09 NOV 2020 
 
 
I agree to implement and conduct the trial 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 CRO and the sponsor in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Ethical Review Committee (ERC) or 
another group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number:  
 
 
 
 
 
 
 

Prot_000.pdf: 
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Clinical Trial Protocol 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Saline-Controlled Trial to Evaluate the Effect of NOV03 
(Perfluorohexyloctane) on Signs and Symptoms of Dry 
Eye Disease Associated with Meibomian Gland 
Dysfunction (Mojave Study) 
Protocol Number: 
904 
Trial Phase: 
3 
Investigational 
Product 
Name: 
NOV03 (100% perfluorohexyloctane) 
IND Number: 
IND 130558 
Indication: 
Dry Eye Disease (keratoconjunctivitis sicca) 
 
  
Investigators: 
Multi-Center 
Sponsor: 
Bausch & Lomb, Incorporated  
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
USA  
Clinical Research 
Organisation: 
IRB/IEC: 
Sterling IRB 
Version: 
2.0 
Original Protocol Date: 
05 AUG 2020 
Amendment 1 Date 
09 NOV 2020 
________________________________________________________________________ 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Bausch & Lomb, Inc. 
Further dissemination, distribution or copying of this protocol or its contents is strictly 
prohibited. 
Regulatory Statement 
This trial will be performed in compliance with the protocol and in accordance with Good 
Clinical Practice (International Conference on Harmonisation [ICH], Guidance E6), 
principles of human subject protection, and applicable country-specific regulatory 
requirements. 


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1 SYNOPSIS AND TRIAL CONTACT INFORMATION 
 
1.1 TRIAL CONTACT INFORMATION 
SPONSOR PERSONNEL 
 
 
 
  
 
  
 
 
MEDICAL MONITOR 
Clinical Research Organization (CRO) PERSONNEL 
 
 
 
 
1.2 SYNOPSIS 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-
Masked, Saline-Controlled Trial to Evaluate the 
Effect of NOV03 (Perfluorohexyloctane) on Signs 
and Symptoms of Dry Eye Disease Associated with 
Meibomian Gland Dysfunction (Mojave Study) 
Protocol Number: 
904 
Investigational Medicinal 
Product: 
NOV03 (100% perfluorohexyloctane) 
Control: 
Saline solution: 0.6% sodium chloride solution  
Trial Phase: 
3 


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Trial Objective: 
The objectives of this trial are to assess the efficacy, 
safety, and tolerability of NOV03 ophthalmic 
solution in comparison to a saline control for the 
treatment of the signs and symptoms of Dry Eye 
Disease (DED) 
 
 
Overall Trial Design 
 
Structure: 
Multi-center, randomized, double-masked, saline-
controlled 
Participant Duration: 
An individual subject’s participation is estimated to 
be approximately 10 weeks. 
Trial Duration: 
The estimated trial duration is approximately 7 
months, from first subject first visit to last subject 
last visit. 
Dosage/Dose Regimen: 
Subjects eligible for randomization will receive one 
of the following treatments to be administered 
bilaterally from Visit 1 to Visit 4. 
1) NOV03 (100% perfluorohexyloctane)  
4 times daily (QID)  
2) Saline solution (0.6% sodium chloride solution) 
4 times daily (QID) 
Summary of Visit Schedule: 
5 visits over the course of approximately 10 weeks 
• Visit 0 = Screening within 14 days before Visit 1 
(Day -14 to -1) 
• Visit 1 = Day 1, Baseline/Randomization 
• Visit 2 = Day 15 ± 1 days, 
• Visit 3 = Day 29 ± 2 days 
• Visit 4 = Day 57 ± 2 days 
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, double-
masked, multi-center trial. Subjects will be 
instructed not to show or discuss the properties of the 
assigned Investigational Medicinal Product (IMP) 
and/or their experience with the IMP with other trial 
participants, and not to show or discuss the IMP with 
the Investigator or site staff other than the dedicated 
dosing coordinator, unless instructed to do so. 
 
A dedicated dosing coordinator at each site will be 
responsible for instructing subjects regarding IMP 
handling/administration, IMP dispensation and 
accountability, reviewing daily dosing diaries, 
performing the instillation comfort questionnaire, 
the Eyedrop acceptability questionnaire and all 
discussions with study subjects related to IMP. 


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Trial Population Characteristics 
Number of Subjects: 
Approximately 760 subjects will be screened to 
enroll at least 560 subjects (280 each arm) at 
approximately 35 clinical sites. 
Condition/Disease: 
Dry Eye Disease (keratoconjunctivitis sicca) 
associated with Meibomian Gland Dysfunction 
Inclusion Criteria: 
Subjects must: 
1. Be at least 18 years of age at the time of consent. 
2. Provide written informed consent. 
3. Have a subject reported history of Dry Eye 
Disease in both eyes for at least 6 months prior 
to Visit 0. 
4. Have Tear film break-up time (TFBUT) ≤5 sec 
at Visit 0 and Visit 1. 
5. Have Ocular Surface Disease Index (OSDI©) 
≥25 at Visit 0 and Visit 1. 
6. Have an unanesthetized Schirmer’s Test I ≥5 
mm at Visit 0 and Visit 1. 
7. 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 0 and Visit 1. 
8. Have a total corneal fluorescein staining score 
of 4 ≤ X ≤11 (i.e. sum of inferior, superior, 
central, nasal, and temporal) according to the 
National Eye Institute (NEI) scale at Visit 0 and 
Visit 1. 
9. Have at least one eye (the same eye) satisfy all 
criteria for 4, 6, 7, and 8 above at Visit 0 and 
Visit 1. 
10. Be able and willing to follow instructions, 
including participation in all trial assessments 
and visits. 
Exclusion Criteria: 
Subjects must not: 
1. Have been randomized in NVU-002, NVU-003, 
or participated in the NVU-004 OLE Study. 
2. Have any clinically significant ocular surface 
slit-lamp findings at Visit 0 and Visit 1 and/or in 
the opinion of the investigator have any findings 
that may interfere with trial parameters and may 
include eye trauma or history of eye trauma or 
anterior membrane dystrophy. 


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3. Have a history of Stevens Johnson Syndrome. 
4. Have 
active 
blepharitis 
or 
lid 
margin 
inflammation 
that 
required 
any 
topical 
antibiotics or topical steroids within last 30 days 
prior to Visit 0 or will likely require such 
treatment during the trial. Any other lid margin 
therapy such as lid scrubs, lid wipes, warm 
compresses, systemic antibiotics (such as 
tetracyclines) and oral supplements for treatment 
of ocular conditions had to be stable within the 
last 30 days prior to Visit 1 and should be 
maintained stable throughout the trial.  
5. Have had a LipiFlow procedure, Intense Pulse 
Light (IPL) procedure or any kind of other 
procedures affecting meibomian glands within 6 
months prior to Visit 1. 
6. Have abnormal lid anatomy that causes 
incomplete eyelid closure including entropion 
and ectropion or floppy lid syndrome that 
exposes parts of the conjunctiva or impairs the 
blinking function of the eye (e.g. Botox 
injections for blepharospasm). 
7. Have received or removed a permanent punctum 
plug within 3 months (6 months for dissolvable 
punctum plugs) prior to Visit 1 or expected to 
receive a punctum plug or removal of a punctum 
plug, or a punctum plug expected to be dissolved 
during the trial.  
8. Have Dry Eye Disease secondary to scarring, 
irradiation, alkali burns, cicatricial pemphigoid, 
or destruction of conjunctival goblet cells (as 
with vitamin A deficiency). 
9. Have an ocular or periocular malignancy.   
10. Have a corneal epithelial defect; have significant 
confluent staining or filaments anywhere on the 
cornea.  
11. Have a history of herpetic keratitis. 
12. Have active ocular allergies or ocular allergies 
that are expected to be active during the trial 
period. 
13. Be diagnosed with an active ocular or systemic 
infection (bacterial, viral, or fungal), including 
fever requiring treatment with antibiotics. 
14. Have worn contact lenses within 1 month of 
Visit 0 or anticipate using contact lenses during 
the trial. 


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15. Have used any eye drops and/or TrueTearTM 
device (Intranasal Tear Neurostimulator) within 
24 hours before Visit 1. 
16. Have had intra-ocular surgery or ocular laser 
surgery within the previous 6 months or have 
any planned ocular and/or lid surgeries over the 
trial period. 
17. Be a family member living in the same 
household of another randomized study 904 or 
NVU-003 subject, or a family member living in 
the same household of another NVU-004 OLE 
participant. 
18. Be a clinical site employee that is directly 
involved in the management, administration, or 
support of this trial or be an immediate family 
member of the same.  
19. Be a woman who is pregnant, nursing or 
planning a pregnancy. 
20. Be unwilling to submit to a urine pregnancy test 
at Visit 0, Visit 1 and Visit 4 (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 bilateral tubal ligation or 
bilateral oophorectomy) or is post-menopausal 
(without menses for 12 consecutive months). 
21. 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 
(IUD); 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 trial, she must agree to use adequate 
birth control as defined above for the remainder 
of the trial. 
22. Have an uncontrolled systemic disease in the 
opinion of the investigator. 
23. Have a known allergy and/or sensitivity to the 
investigational drug or saline components.  


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24. Have active ocular or periocular rosacea that in 
the judgement of the investigator interferes with 
the trial (e.g, clinically relevant lid induration).  
25. Have a pterygium in any eye.  
26. Be currently enrolled in an investigational drug 
or device study or have used an investigational 
drug or device within 60 days of Visit 1. 
27. Have used any topical ocular steroids treatments, 
topical cyclosporine, lifitegrast, serum tears or 
topical anti-glaucoma medication within 60 days 
prior to Visit 0. 
28. Have 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 0 or expected to be 
unstable during the trial. 
29. Have corrected visual acuity worse than or equal 
to logarithm of the minimum angle of resolution 
(logMAR), +0.7 as assessed with Early 
Treatment of Diabetic Retinopathy Study 
(ETDRS) charts in both eyes at Visit 0 and 
Visit 1. 
30. Have a condition or be in a situation (including 
language barrier) which the investigator feels 
may put the subject at significant risk, may 
confound the trial results, or may interfere 
significantly with the subject’s participation in 
the trial. 
31. Have a history of isotretinoin (e.g. Accutane, 
Myorisan, Claravis, Amnesteem) use. 
Trial Formulations: 
• 100% Perfluorohexyloctane  
• Saline Solution (0.6% sodium chloride solution) 
Evaluation Criteria 
 
Efficacy Endpoint(s):  
Primary Efficacy Endpoints: 
The following primary endpoints will be tested 
using a hierarchical fixed sequence testing to 
maintain an overall two-sided alpha = 0.05 level: 
 
1. Change from baseline (CFB) in total Corneal 
Fluorescein Staining (tCFS) (NEI scale) at 
Day 57 
2. CFB of Dryness Score (visual analogue scale 
[VAS] Severity of Dryness) at Day 57 
 
Secondary Efficacy Endpoints: 


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If both primary endpoints demonstrate statistically 
significant superiority of NOV03 versus saline at the 
two-sided alpha = 0.05 level, the following 
secondary endpoints will be tested hierarchically to 
maintain an overall two-sided alpha = 0.05. 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining 
(tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining 
(cCFS) (NEI scale) at Day 57 
 
Other Pre-specified Efficacy Endpoints 
1. CFB of Dryness Score (VAS) at Day 29  
2. CFB in tCFS at Day 29  
3. CFB in CFS central and inferior sub-regions 
(NEI scale) to each measured post-baseline visit. 
4. Proportion of tCFS responders (≥3 improvement 
based on NEI scale) at Day 57. 
5. Proportion of Dryness Score responders (≥30 % 
improvement from baseline) at Day 57. 
6. CFB in VAS burning/stinging, sticky feeling, 
foreign body sensation, itching, blurred vision, 
sensitivity to light, pain, frequency of dryness, 
and awareness of dry eye symptoms at each 
measured post-baseline visit. 
7. CFB in Ocular Surface Disease Index (OSDI©) 
at each measured post-baseline visit. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Safety Endpoints: 
1. Ocular and non-ocular Treatment Emergent 
Adverse Events (TEAEs) 
2. Visual Acuity 
3. Slit-Lamp Biomicroscopy  
4. Intraocular Pressure  
5. Dilated Fundoscopy  
 
 
 
 
 
General Statistical Methods and Types of Analyses 


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The primary endpoints will be tested in a hierarchical fixed sequence in the following 
order. 
 
The statistical hypotheses for the primary endpoint of CFB corneal fluorescein 
staining (NEI scale) total score at Day 57 are as follows: 
 
H01: 
The difference, between study eyes treated with NOV03 and study 
eyes treated with saline, in the mean CFB corneal fluorescein staining 
(NEI scale) total score at Day 57 = 0. 
 
HA1:  The difference, between study eyes treated with NOV03 and study 
eyes treated with saline, in the mean CFB corneal fluorescein staining 
(NEI scale) total score at Day 57 ≠ 0, with superiority claimed if the 
difference is less than 0 (NOV03 minus saline). 
 
The statistical hypotheses for the hierarchical primary endpoint of the CFB Dryness 
Score (VAS) at Day 57 are as follows: 
 
H02: 
The difference, between subjects treated with NOV03 and subjects 
treated with saline, in the mean CFB Dryness Score (VAS) at Day 57= 
0. 
 
HA2: 
The difference, between subjects treated with NOV03 and subjects 
treated with saline, in the mean CFB Dryness Score (VAS) at Day 57 ≠ 
0, with superiority claimed if the difference is less than 0 (NOV03 
minus saline). 
The study has been designed to have 95% power to reject both H01 and H02 assuming 
independence between the sign and symptom endpoint; positive correlation between 
these two endpoints would increase the overall power. 
Estimated mean differences (common standard deviations) in CFB to Day 57 using an 
ANCOVA analysis with CFB to Day 57 as the response, baseline as a covariate and 
treatment as the fixed effect from NVU-002 are: -1.2 (2.5) for tCFS and -11 (26) for 
Dryness Score. Conservative estimates of -1.0 (2.8) for tCFS and -10 (28) for Dryness 
Score are used for sample size calculation. 
 
Two hundred fifty (250) subjects (study eyes) per treatment group yields 97.9% power 
to reject H01 in favor of HA1 and conclude superiority of NOV03 over saline in the mean 
CFB tCFS score at Day 57 assuming a true difference (NOV03 minus saline) of -1.0, a 
common standard deviation of 2.8, and a two-sided alpha = 0.05. Two hundred fifty 
(250) subjects per treatment group yields 97.9% power to reject H02 in favor of HA2 and 
conclude superiority of NOV03 over saline in the mean CFB Dryness Score (VAS) at 
Day 57 assuming a true difference (NOV03 minus saline) of -10, a common standard 
deviation of 28, and a two-sided alpha = 0.05. Accounting for an assumed 10% subject 
discontinuation rate, approximately 560 subjects (280 subject each arm) will be 


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randomly assigned to trial treatment such that approximately 250 evaluable participants 
per arm complete the trial. 
 
Therefore, assuming independence between tCFS score and Dryness Score (VAS), 250 
FAS subjects per treatment group at Day 57 yields 97.9%* 97.9%= 95.8% power to 
reject both H01 and H02. 
 
Hierarchical fixed sequence testing will be employed to maintain the type I error rate. 
The primary analyses will first test the difference in the mean CFB corneal fluorescein 
staining (NEI scale) total score between treatments at Day 57. If the test of the 
difference is statistically significant at the two-sided alpha = 0.05 level in favor of 
NOV03 then the trial will be considered a success; NOV03 will be declared to be 
superior to saline in the mean CFB corneal fluorescein staining (NEI scale) total score 
at Day 57; and the difference in the mean CFB total Dryness Score between treatments 
at Day 57 will be tested at the two-sided alpha = 0.05 level. 
 
If in addition to a statistically significant test of the difference in the mean CFB corneal 
fluorescein staining (NEI scale) total score at Day 57 is in favor of NOV03, and the test 
of the difference in the mean change from Dryness Score at Day 57 is also statistically 
significant in favor of NOV03, then NOV03 will be declared to be superior to saline in 
both the mean CFB corneal fluorescein staining (NEI scale) total score and the mean 
CFB of the Dryness Score at Day 57. 
 
If both primary endpoints demonstrate statistically significant superiority of NOV03 
versus saline at the two-sided alpha = 0.05 level, a hierarchical testing of the secondary 
endpoints will be performed.  
 
Primary Efficacy Analyses:  
The primary comparison in this trial will be between NOV03 versus saline at Day 57. 
The primary efficacy endpoints (e.g. CFB in total corneal fluorescein staining [NEI 
scale] and Dryness Score [VAS]) will be summarized descriptively (n, mean, standard 
deviation, median, min, and max) and analyzed separately using an ANCOVA model 
with terms for baseline value, and treatment. 
Least squares mean for each treatment group and for the difference between treatment 
groups will be presented from each model together with two-sided p-values (used for 
primary inference) and 95% confidence intervals. 
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures 
analysis comparing treatment groups will be performed as sensitivity analyses. 
The primary analysis of the primary endpoints will use the Full Analysis Set (FAS) 
with available data per subject, assuming the overall study discontinuation rate is <5%. 
If the overall study discontinuation rate is ≥5% then the primary analysis will be based 
on primary imputation methodology as detailed in the statistical analysis section and 
the available data analyses will become robustness analyses. 


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Additional robustness analyses will include repeating the primary analysis on the per 
protocol set (PPS); the FAS imputing missing data using last observation carried 
forward (LOCF); the FAS imputing missing data using Markov Chain Monte Carlo 
(MCMC) multiple imputation methodology under different assumptions of 
missingness (at random and not at random) each using 30 imputed values.  
 
Further Efficacy Analyses: 
The following secondary endpoints will be tested hierarchically: 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
 
Inference will only be made on these endpoints, at a 2-sided alpha = 0.05, if both 
primary endpoints and any higher order secondary endpoints are statistically significant 
at a 2-sided alpha = 0.05 in favor of NOV03. 
 
The primary analysis of the secondary endpoints will use the Full Analysis Set (FAS) 
with available data per subject, assuming the overall study discontinuation rate is <5%. 
If the overall study discontinuation rate is ≥5%, then the primary analysis of the 
secondary endpoints will follow the same imputation strategy detailed for the primary 
endpoints. 
Quantitative secondary and other pre-specified efficacy endpoints will be summarized 
descriptively (n, mean, standard deviation, median, min and max) by visit, and analyzed 
similarly to the primary endpoint at each measured visit and CFB. Least squares mean 
for each treatment group and for the difference between treatment groups will be 
presented from the model together with two-sided p-values and 95% confidence 
intervals.  
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures 
analysis will also be presented as sensitivity analyses. The other pre-specified analyses 
will use the Full Analysis Set (FAS) with available data per subject. 
Other pre-specified endpoints evaluating the proportion of study eyes (or subjects) 
meeting pre-defined criteria will be presented and tested between treatment groups 
using logistic regression analysis adjusting for baseline tCFS score at each measured 
follow-up visit. Pearson chi-squared analysis comparing the treatment groups will be 
performed as sensitivity analyses.  
 
Safety Variables: 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and 
percentages of subjects with treatment-emergent adverse events (TEAEs), serious 
TEAEs, and TEAEs causing premature discontinuation will be provided by treatment 


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group. An AE is treatment emergent if it occurs or worsens after the first dose of trial 
treatment. Furthermore, frequencies will be given of subjects with TEAEs by system 
organ class; by system organ class and preferred term; by system organ class, preferred 
term and maximal severity; by system organ class, preferred term and strongest 
relationship; and by system organ class, preferred term, maximal severity, and strongest 
relationship. Separate summaries will be performed for ocular and non-ocular TEAEs. 
Other safety endpoints including assessments of visual acuity, slit-lamp biomicroscopy, 
dilated fundoscopy, and intraocular pressure will be summarized by treatment group 
and visit using descriptive statistics. Changes from baseline will also be summarized 
where appropriate. For assessments performed by eye, study eye and fellow eye will 
be summarized separately.  
 
 
 


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TABLE OF CONTENTS 
 
1 
SYNOPSIS AND TRIAL CONTACT INFORMATION ..................................... 2 
1.1 
TRIAL CONTACT INFORMATION .................................................................. 2 
1.2 
SYNOPSIS............................................................................................................... 2 
TABLE OF CONTENTS................................................................................................ 13 
LIST OF ABBREVIATIONS ........................................................................................ 17 
2 
INTRODUCTION .................................................................................................. 19 
2.1 
Dry Eye Disease (DED) ........................................................................................ 19 
2.2 
Product Rationale ................................................................................................. 19 
2.3 
Trial Rationale ...................................................................................................... 20 
2.4 
Summary of Known and Potential Risks and Benefits to Human Subjects ... 21 
3 
TRIAL OBJECTIVES ........................................................................................... 22 
3.1 
Primary Objective ................................................................................................ 22 
3.2 
Secondary Objectives ........................................................................................... 22 
4 
TRIAL DESIGN ..................................................................................................... 22 
4.1 
Overall Trial Design ............................................................................................. 22 
4.2 
End of Trial Definition ......................................................................................... 23 
4.3 
Visit Description ................................................................................................... 23 
4.4 
Enrollment and Treatment Assignment ............................................................. 24 
4.5 
Justification of Trial Design ................................................................................ 25 
4.6 
Justification of Dose ............................................................................................. 26 
5 
TRIAL POPULATION ......................................................................................... 26 
5.1 
Number of Subjects (approximate) ..................................................................... 26 
5.2 
Trial population characteristics .......................................................................... 26 
5.3 
Inclusion Criteria.................................................................................................. 26 
5.4 
Exclusion Criteria ................................................................................................. 27 
5.5 
Re-Screen Procedures .......................................................................................... 29 
5.6 
Subject/Trial Withdrawal Criteria ..................................................................... 29 
6 
TRIAL PARAMETERS ........................................................................................ 30 
6.1 
Efficacy Endpoints................................................................................................ 30 
6.1.1 
Primary Efficacy Endpoints: ............................................................ 30 
6.1.2 
Secondary Efficacy Endpoints: ........................................................ 30 
6.1.3 
Other Pre-specified Efficacy Endpoints:.......................................... 30 
6.1.4 
Exploratory Efficacy Endpoints: ...................................................... 30 
6.2 
Safety Endpoints ................................................................................................... 31 
6.3 
Other Endpoints ................................................................................................... 31 
7 
TRIAL MATERIALS ............................................................................................ 32 
7.1 
Investigational Medicinal Product(s) .................................................................. 32 
7.1.1 
IMP(s)/ Formulation (s) ................................................................... 32 
7.1.2 
Labeling and Packaging of IMP....................................................... 32 
7.1.3 
IMP Storage ..................................................................................... 33 
7.1.4 
IMP Dispensation ............................................................................. 33 
7.1.5 
Instructions for Use and Administration .......................................... 33 


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7.2 
IMP Accountability .............................................................................................. 34 
7.3 
IMP Handling and Return ................................................................................... 35 
7.4 
IMP Masking ........................................................................................................ 35 
7.5 
Other Trial Supplies ............................................................................................. 35 
8 
TRIAL METHODS AND PROCEDURES ......................................................... 36 
8.1 
Concurrent Medications and Therapies ............................................................. 36 
8.2 
Prohibited Medications ........................................................................................ 36 
8.3 
Restrictions and Prohibitions .............................................................................. 37 
8.4 
Examination Procedures ...................................................................................... 37 
8.4.1 
Procedures to be performed at each trial visit with regard to trial 
objective(s) .................................................................................................... 37 
8.4.2 
Early Termination/Discontinuation.................................................. 39 
8.4.3 
Unscheduled Visits .......................................................................... 40 
8.5 
Compliance with Protocol .................................................................................... 40 
8.6 
Subject Disposition ............................................................................................... 40 
8.6.1 
Completed Subjects.......................................................................... 40 
8.6.2 
Discontinued subjects ...................................................................... 41 
8.7 
Trial Termination ................................................................................................. 41 
8.8 
Trial Duration ....................................................................................................... 41 
9 
ADVERSE EVENTS.............................................................................................. 42 
9.1 
Adverse Event ....................................................................................................... 42 
9.1.1 
Severity ............................................................................................ 42 
9.1.2 
Relationship to Investigational Product ........................................... 43 
9.1.3 
Expectedness .................................................................................... 43 
9.1.4 
Outcome ........................................................................................... 43 
9.2 
Serious Adverse Events ........................................................................................ 44 
9.3 
Procedures for Reporting Serious Adverse Events ........................................... 45 
9.3.1 
Reporting a Serious Adverse Event ................................................. 45 
9.3.2 
Reporting a Suspected Unexpected Serious Adverse Reaction 
(SUSAR)........................................................................................................ 46 
9.4 
Procedures for Unmasking of IMP ..................................................................... 46 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events .......... 46 
9.6 
Reporting Pregnancies ......................................................................................... 47 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ............... 48 
10.1 Analysis Populations ............................................................................................ 48 
10.2 Statistical Hypotheses ........................................................................................... 48 
10.3 Sample Size............................................................................................................ 49 
10.4 Statistical Analysis ................................................................................................ 50 
10.4.1 General Considerations .................................................................... 50 
10.4.2 Unit of Analysis ............................................................................... 50 
10.4.3 Missing Data .................................................................................... 50 
10.4.4 Multiplicity Consideration ............................................................... 51 
10.4.5 Primary Efficacy Analyses............................................................... 51 
10.4.6 Secondary Efficacy Analyses........................................................... 53 
10.4.7 Other Pre-specified Efficacy Analyses ............................................ 53 
10.4.8 Exploratory Analyses ....................................................................... 54 
10.4.9 Other Analyses ................................................................................. 54 


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10.4.10 Safety Variables Analyses ............................................................... 54 
10.4.11 Interim Analyses .............................................................................. 55 
10.5 Additional Analyses .............................................................................................. 55 
10.6 Methods to Minimize Bias ................................................................................... 55 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ............................... 56 
11.1 Protection of Human Subjects ............................................................................. 56 
11.1.1 Subject Informed Consent ................................................................ 56 
11.1.2 Institutional Review Board (IRB) Approval .................................... 56 
11.2 Ethical Conduct of the Trial ................................................................................ 56 
11.3 Subject Confidentiality ........................................................................................ 56 
11.4 Documentation ...................................................................................................... 57 
11.4.1 Retention of Documentation ............................................................ 57 
11.5 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) .................................................................................................................. 57 
11.6 Monitoring and Quality Assurance .................................................................... 58 
11.7 Handling of Biological Specimens ....................................................................... 58 
11.8 Publications ........................................................................................................... 58 
12 
REFERENCES ....................................................................................................... 59 
13 
APPENDICES ........................................................................................................ 60 
Appendix 1 Schedule of Assessments (in recommended order) ................................. 60 
Appendix 2 Instructions for Administration of Eye Drops ......................................... 61 
Appendix 3 Examination Procedures, Tests, Equipment, and Techniques ............... 63 
Appendix 4 Amendment Summary of Changes ........................................................... 73 
Appendix 5 Sponsor and CRO Approvals .................................................................... 74 
Appendix 6 Investigator’s Signature ............................................................................. 75 
 
 
 
 


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LIST OF TABLES 
 
Table 1 
Active Investigational Product ....................................................................... 32 
Table 2 
Control Investigational Product ...................................................................... 32 
 
 
LIST OF FIGURES 
Figure 1 
Study 904 Flow Chart ..................................................................................... 24 
 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Assessments (in recommended order)........................................ 60 
Appendix 2 Instructions for Administration of Eye Drops ................................................ 61 
Appendix 3 Examination Procedures, Tests, Equipment, and Techniques ....................... 63 
Appendix 4 Amendment Summary of Changes ................................................................ 73 
Appendix 5 Sponsor and CRO Approvals ......................................................................... 74 
Appendix 6 Investigator’s Signature.................................................................................. 75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCVA 
Best-corrected Visual Acuity 
BID 
Two times daily 
BOCF 
Baseline Observation Carried Forward 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CFS 
Corneal Fluorescein Staining 
cCFS 
Central Corneal Fluorescein Staining 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
DED 
Dry Eye Disease 
DEWS 
Dry Eye Workshop 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capturing system 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug  
IOP 
Intraocular Pressure 
IRB 
Institutional/Independent Review Board 
IPL 
Intense Pulse Light 
IUD 
Intra-Uterine Device 
IRS 
Interactive Response System 
logMAR 
logarithm of the Minimum Angle of Resolution 
LOCF 
Last Observation Carried Forward 
LSLV 
Last Subject Last Visit 
MCMC 
Markov Chain Monte Carlo  
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
Meibomian Gland Dysfunction 
NEI 
National Eye Institute 
NOV03 
100% perfluorohexyloctane 
OD 
right eye 
OS 
left eye 
OSDI© 
Ocular Surface Disease Index 


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PPS 
Per Protocol Set 
QID 
Four times a day 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SMP 
Safety Management Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAEs 
Treatment-emergent Adverse Events 
tCFS 
total Corneal Fluorescein Staining 
TFBUT 
Tear Film Break-up Time 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
 
 


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2 INTRODUCTION 
2.1 Dry Eye Disease (DED) 
Dry Eye Disease (DED) is defined by the International Dry Eye Workshop (DEWS) as a 
multifactorial disease of the ocular surface characterized by a loss of homeostasis of the 
tear film, and accompanied by ocular symptoms, in which tear film instability and 
hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities 
play etiological roles (Craig et al., 2017). Symptoms of DED such as feeling of dryness, 
burning, a sandy/gritty sensation, foreign body sensation, pain or itchiness are quite 
debilitating. In addition, visual function related symptoms such as fluctuating vision with 
blinking, blurred vision, and difficulty with reading despite perfect visual acuity is an 
important and underestimated aspect of the disease. In consequence, DED negatively 
impacts quality of life comparably to other severe diseases (Schiffman et al., 2003), and 
adverse effects on mental health, such as depression and anxiety, have been observed (Le 
et al., 2012). DED is a serious and chronic disorder that, if left untreated or undertreated, 
progressively damages the ocular surface and may lead to permanent vision loss due to 
corneal complications (Lemp et al., 1995). 
 
As many as 5 - 35% of subjects visiting ophthalmic clinics report dry eye symptoms, 
making it one of the most common conditions seen by ophthalmic specialists (McCarty et 
al., 1998; Lin et al., 2003). Estimates of the prevalence of dry eye vary considerably, 
depending on the criteria used to define the disease, but in the United States (US), it has 
been estimated that as many as 3.2 million women and 1.7 million men over the age of 50 
have DED, with a projected 40% increase in the number of patients affected by 2030 
(Schaumberg et al., 2002; Schaumberg et al., 2003; Schaumberg et al., 2009) With the aging 
population in the US and other countries of the developed world, and with increasing 
computer use, DED is expected to continue to become more prevalent and finding a 
treatment is becoming more important (Benitez-del-Castillo et al., 2017).  
2.2 Product Rationale 
NOV03 is a sterile ophthalmic eye drop formulation, developed for the treatment of the 
signs and symptoms of DED 
 
 
It is a single component product consisting of 100% perfluorohexyloctane. NOV03 
addresses DED associated with MGD via a new physicochemical mode of action. Due to 
its low surface tension it rapidly spreads across the ocular surface and interacts with the 
lipophilic part of the tear film forming a layer at the tear film air interface. Such a layer 
prevents excessive evaporation of the aqueous tear film component. 
 
 
. As a water-free, single component product, it is free 
of excipients like oils, surfactants and preservatives. Related advantages include convenient 
handling, improved tolerability, and a decrease in the visual disturbance upon instillations. 
Due to this mode of action subjects with DED associated with MGD were considered to 
experience the greatest benefit from the treatment. This is in line with experience from the 




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2.4 Summary of Known and Potential Risks and Benefits to Human Subjects  
The active and only ingredient of NOV03, perfluorohexyloctane, is a semifluorinated 
alkane with a well-established tolerability and safety profile. 
 
 
 
 
 
 
 
 
It is not yet approved in the US.  
 
Safety data from the NVU-002 trial showed an excellent clinical safety and tolerability 
profile. No remarkable imbalance in terms of treatment emergent adverse events (TEAEs) 
across treatment groups were revealed. Incidence of ocular AEs was low, ranging from 
4.5% to 11.7%, and the great majority were of mild intensity. Instillation site reactions were 
reported in single cases in 3 (2.6%) subjects in NOV03 QID, 1 (0.9%) subject in NOV03 
BID and 2 (1.8%) subjects in the saline group. A total of 4 serious adverse events (SAEs) 
were reported in 4 subjects. Three (3) subjects were randomized to the NOV03 QID group 
and 1 subject was randomized to the NOV03 BID group. All SAEs were non-ocular and 
not related to trial treatment. All SAEs resolved. 
 
Slit-lamp biomicroscopy, dilated fundoscopy, mean best corrected visual acuity (BCVA) 
and intraocular pressure (IOP) observations did not indicate any treatment-related changes. 
There were no clinically significant changes in vital signs, laboratory parameters or other 
observations related to safety. 
 
Up to now four AEs of blurred vision have been reported, two were assessed as not related 
and two as related. If any visual disturbances should occur upon instillation of the drop the 
subject is advised not to drive or use machines until such effects have disappeared. 
 
 
 
 
 
 
 
 
 
 
As described in Section 2.3 the NVU-002 trial demonstrated a favorable efficacy in 
reducing signs and symptoms of DED in subjects with evaporative forms of DED
 
. This efficacy profile is supported by experience from the Post Market Clinical 
Follow-up studies. 
In summary, based on the preclinical and clinical data obtained to date, risks to subjects in 
the planned NVU-003 trial are considered very low. Furthermore, the subjects randomized 
in this trial will be closely monitored, and current standard ophthalmological safety 
assessments will be performed during the entire treatment period.  


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The efficacy demonstrated to date shows that NOV03 reduces DED signs as well as DED 
symptoms stronger than the saline comparator in the target population of subjects with DED 
  
NOV03 therefore provides a favorable benefit-risk treatment profile to subjects with DED 
 The study 904 trial is designed to replicate the results of the NVU-
003 study and confirm the positive benefit-risk profile. 
 
3 TRIAL OBJECTIVES 
3.1 Primary Objective 
• The primary objective of this trial is to assess the efficacy of NOV03 
(perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in comparison 
to a saline control for the treatment of the signs and symptoms of Dry Eye Disease 
associated with MGD. 
 
3.2 Secondary Objectives 
• The secondary objective of this trial is to assess the safety and tolerability of NOV03 
(perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in comparison 
to a saline control in subjects with Dry Eye Disease associated with MGD. 
 
• Further objectives of this trial are to explore the effect on other efficacy endpoints of 
NOV03 (perfluorohexyloctane) ophthalmic solution at a QID dosing regimen in 
comparison to a saline control in subjects with Dry Eye Disease associated with 
MGD. 
 
4 TRIAL DESIGN 
4.1 Overall Trial Design 
This trial is a phase 3, multi-center, randomized, double-masked, saline-controlled trial to 
evaluate the effect of NOV03 (100% perfluorohexyloctane) at a QID dosing regimen on 
signs and symptoms of Dry Eye Disease. Approximately 560 male and female subjects (280 
each arm) of at least 18 years of age with a subject-reported history of DED in both eyes 
and who meet all other trial eligibility criteria will be randomized, stratified by clinical site 
and dryness score <70 vs ≥ 70 (VAS) at baseline, 1:1 to receive 1 of 2 treatments: 
Treatment 1: NOV03 (100% perfluorohexyloctane), 4 times daily (QID) 
Treatment 2: Saline (0.6% sodium chloride solution), QID 


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Each treatment group will be comprised of 280 subjects such that approximately 250 
evaluable subjects per arm complete the trial. Approximately 35 clinical sites are 
anticipated to participate. 
 
This trial will consist of two periods: Up to 14-day screening period and a 57-day treatment 
period (See Appendix 1).  
 
4.2 End of Trial Definition  
The end of the trial for an individual subject is defined as that subject’s last clinic visit or 
the date of early termination, if applicable. For subjects that are lost to follow-up, the date 
of early termination will be the date of the last attended clinic visit. The end of the trial for 
the overall trial is defined as completion of the last visit or procedure as specified in 
schedule of assessments for all subjects in the trial. 
 
4.3 Visit Description  
Subjects will be required to sign an Informed Consent before completing any trial related 
procedures. All trial procedures are listed in Section 8.4 and in the schedule of assessments 
(see Appendix 1). The ocular symptoms assessments and evaluations must be performed in 
the respective order as listed. IMP Dispensation is described in Section 7.1.4. 
 
Subjects will be instructed not to show or discuss the properties of the assigned IMP and/or 
their experience with the IMP with other trial participants, and not to show or discuss the 
IMP with the Investigator or site staff other than the dedicated dosing coordinator, unless 
instructed to do so. 
 
Screening (Visit 0) 
 
All assessments required for the screening visit must be done within 14 days before the 
randomization, baseline Visit 1. At least one eye must qualify with all of the following 
objective measures: Tear film break up time ≤5 sec, Schirmer’s Test ≥5 mm, Meibomian 
gland dysfunction (MGD) defined as MGD score ≥ 3, and total Corneal Fluorescein 
Staining (CFS) of 4≤x≤11. Subjects who fail to qualify for the trial at screening may be 
rescreened as described in Section 5.5. 
Baseline Day 1 (Visit 1) 
On Day 1 (Visit 1), eligible subjects will be evaluated for baseline signs and symptoms of 
dry eye disease and will be randomized to NOV03 QID or saline solution QID. Subjects 
will be given a 14-day supply and will self-administer a single drop of the first initial trial 
medication into each eye at the clinic. Subsequently the subject will be asked to complete 
an instillation comfort questionnaire. Each subject will be given a dosing diary to record 


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dosing. Study staff will help the subject to understand how to use the dosing diary and when 
the remaining doses should be taken. 
Visits 2-4 / (ET) 
Subjects will return to the clinic on Day 15±1 (Visit 2), 29±2 (Visit 3), and 57±2 (Visit 
4/Early Termination (ET)) to be evaluated for signs and symptoms of dry eye disease. The 
subject will be asked to complete an eyedrop acceptability questionnaire during Visit 4. 
Collection and review of IMP will be performed (used and unused trial medication should 
be returned to the clinic) and new trial medication will be dispensed at Visit 2 and Visit 3. 
The dosing diary will be collected at the clinic during each visit and checked for 
compliance. Subjects will be discharged from the trial after all Visit 4/ET assessments have 
been completed. 
Early Termination 
Subjects who terminate early during the treatment period will be asked to complete all 
assessments as indicated at Visit 4 on the schedule of assessments prior to commencement 
of any alternative dry eye therapy (if considered possible). Subjects who are terminated 
early from the trial will not be replaced. 
Trial Flow  
All subjects will be expected to progress from screening through trial exit. All subjects will 
follow the trial structure as shown in Figure 1. 
 
 
 
Figure 1 
Study 904 Flow Chart 
 
4.4 Enrollment and Treatment Assignment  
All treatment groups will be enrolled in parallel. Each subject will be assigned a unique 
subject number. All subject numbers will be assigned by Interactive Response System (IRS) 
in strict numerical sequence and no numbers will be skipped or omitted. If all eligibility 
criteria are met at Visits 0 and 1, each qualifying subject will then be randomized.  


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Site and Dryness Score <70 vs ≥ 70 (VAS) at baseline (Visit 1) are used as a stratification 
factor in this trial. IRS will be used to account for the stratification factors while assigning 
the drug kit numbers at visits 1, 2 and 3. The subjects, investigators, Clinical Research 
Organization (CRO) personnel involved in conduct and monitoring of the trial and sponsor 
will be masked to IMP assignment. 
Each subject will participate in the trial for approximately 10 weeks. The total duration of 
the trial from First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV) is 
expected to be approximately 7 months. 
 
4.5 Justification of Trial Design 
This trial is designed as a confirmatory trial to the previously conducted phase 2 trial NVU-
002 and a supportive trial to the ongoing phase 3 trial NVU-003 in subjects with DED 
associated with MGD. This population is considered to respond best based on the mode of 
action and clinical data. 
 
The trial will be a randomized, double-masked, saline controlled trial to demonstrate 
efficacy and safety of NOV03 after a 2-month treatment duration. Vehicle controlled trials 
are currently the standard for DED trials, however, as NOV03 is a 100% single component 
product, saline solution has been selected as comparator given that this most likely best 
reflects a placebo treatment. Randomization and double masking are state of the art 
measures to reduce bias. Fast onset of efficacy is important for subjects and their 
compliance to therapies, thus early demonstration of efficacy (e.g. at 2 month) is desired 
and highly clinically relevant. Moreover, DED is a fluctuating condition with recurring dry 
eye complaints that may be linked to seasonal and/ or environmental changes (Van Setten 
et al., 2016), thus a primary endpoint assessment following a shorter treatment duration is 
considered clinically relevant and has a greater potential to capture the true drug effect. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The two primary endpoints, tCFS and Dryness Score, will be tested in a hierarchical order 
with total corneal fluorescein staining being tested first as the NVU-002 data for this 
endpoint is stronger. The hierarchical testing has been selected to protect the α – error.  
 
4.6 Justification of Dose  
The NOV03 QID dosing regimen to be evaluated in this trial is based on the results from 
the phase 2 NVU-002 trial. The QID regimen showed more pronounced reductions in tCFS 
and symptom scores as measured by OSDI and VAS. This was confirmed by responder 
analyses on signs (tCFS) as well as symptoms (Dryness Score) that underlined the relevance 
of these observed changes.  
 
Based on the safety and tolerability profile seen for both treatment regimens in NVU-002 
and the consistent trend for better efficacy in NOV03 QID in both signs and symptoms the 
QID dose regimen will be tested in this trial. The aim of the current trial study 904 is to 
replicate the efficacy and safety results of NVU-002 and to provide additional supportive 
data in addition to the phase 3 trial NVU-003. 
 
5 TRIAL POPULATION 
5.1 Number of Subjects (approximate) 
An estimated 760 subjects will be screened to randomly assign at least 560 subjects to 
IMP such that approximately 250 evaluable subjects per treatment arm complete the trial. 
 
5.2 Trial population characteristics 
All subjects must be at least 18 years of age, of either gender and any race. Subjects must 
have a reported history of dry eye in both eyes and meet all inclusion criteria and none of 
the exclusion criteria. 
 
5.3 Inclusion Criteria 
Subjects will be eligible to participate in this trial if they meet all following criteria:  
1. Be at least 18 years of age at the time of consent. 
2. Provide written informed consent. 
3. Have a subject reported history of Dry Eye Disease in both eyes for at least 6 months 
prior to Visit 0. 
4. Have Tear film break-up time (TFBUT) ≤5 sec at Visit 0 and Visit 1. 
5. Have Ocular Surface Disease Index (OSDI©) ≥25 at Visit 0 and Visit 1. 
6. Have an unanesthetized Schirmer’s Test I ≥5 mm at Visit 0 and Visit 1. 
7. 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 


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from 0-3; 0 = normal, 1 = thick/yellow, whitish, particulate 2 = paste; 3 = 
none/occluded; total score will range from 0-15) at Visit 0 and Visit 1. 
8. Have a total corneal fluorescein staining score of 4≤ X ≤11 (i.e. sum of inferior, 
superior, central, nasal, and temporal) according to the National Eye Institute (NEI) 
scale at Visit 0 and Visit 1.   
9. Have at least one eye (the same eye) satisfy all criteria for 4, 6, 7, and 8 above at Visit 
0 and Visit 1. 
10. Be able and willing to follow instructions, including participation in all trial 
assessments and visits. 
 
5.4 Exclusion Criteria 
Subjects will not be eligible to participate in this trial if any of the following criteria apply: 
1. Have been randomized in NVU-002, NVU-003 or participated in the NVU-004 OLE 
Study. 
2. Have any clinically significant ocular surface slit-lamp findings at Visit 0 and Visit 1 
and/or in the opinion of the investigator have any findings that may interfere with trial 
parameters and may include eye trauma, history of eye trauma or anterior membrane 
dystrophy. 
3. Have a history of Stevens Johnson Syndrome. 
4. Have active blepharitis or lid margin inflammation that required any topical antibiotics 
or topical steroids within last 30 days prior to Visit 0 or will require such treatment 
during the trial. Any other lid margin therapy such as lid scrubs, lid wipes, warm 
compresses, systemic antibiotics (such as tetracyclines) and oral supplements for 
treatment of ocular conditions or oral supplements had to be stable within the last 30 
days prior to Visit 1 and should be maintained stable throughout the trial.  
5. Have had a LipiFlow procedure, Intense Pulse Light (IPL) procedure or any kind of 
other procedures affecting meibomian glands within 6 months prior to Visit 1. 
6. Have abnormal lid anatomy that causes incomplete eyelid closure including entropion 
and ectropion or floppy lid syndrome that exposes parts of the conjunctiva or impairs 
the blinking function of the eye (e.g. Botox injections for blepharospasm). 
7. Have received or removed a permanent punctum plug within 3 months (6 months for 
dissolvable punctum plugs) prior to Visit 1 or expected to receive a punctum plug or 
removal of a punctum plug, or a punctum plug expected to be dissolved during the trial.  
8. Have Dry Eye Disease secondary to scarring, irradiation, alkali burns, cicatricial 
pemphigoid, or destruction of conjunctival goblet cells (as with vitamin A deficiency). 
9. Have an ocular or periocular malignancy. 
10. Have a corneal epithelial defect; have significant confluent staining or filaments 
anywhere on the cornea.  
11. Have a history of herpetic keratitis. 
12. Have active ocular allergies or ocular allergies that are expected to be active during the 
trial period. 
13. Be diagnosed with an active ocular or systemic infection (bacterial, viral, or fungal), 
including fever requiring treatment with antibiotics. 


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14. Have worn contact lenses within 1 month of Visit 0 or anticipate using contact lenses 
during the trial. 
15. Have used any eye drops and/or TrueTearTM device (Intranasal Tear Neurostimulator) 
within 24 hours before Visit 1. 
16. Have had intra-ocular surgery or ocular laser surgery within the previous 6 months or 
have any planned ocular and/or lid surgeries over the trial period. 
17. Be a family member living in the same household of another randomized study 904 or 
NVU-003 subject, or a family member living in the same household of another NVU-
004 OLE participant. 
18. Be a clinical site employee that is directly involved in the management, administration, 
or support of this trial or be an immediate family member of the same.  
19. Be a woman who is pregnant, nursing or planning a pregnancy. 
20. Be unwilling to submit to a urine pregnancy test at Visit 0, Visit 1 and Visit 4 (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 bilateral tubal 
ligation or bilateral oophorectomy) or is post-menopausal (without menses for 12 
consecutive months). 
21. 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 (IUD); 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 trial, she must agree to use adequate birth control as defined above for the 
remainder of the trial. 
22. Have an uncontrolled systemic disease in the opinion of the investigator. 
23. Have a known allergy and/or sensitivity to the investigational drug or saline 
components.  
24. Have active ocular or periocular rosacea that in the judgement of the investigator 
interferes with the trial (e.g., clinically relevant lid induration). 
25. Have pterygium in any eye. 
26. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 60 days of Visit 1. 
27. Have used any topical ocular steroids treatments, topical cyclosporine, lifitegrast, 
serum tears or topical anti-glaucoma medication within 60 days prior to Visit 0. 
28. Have 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 0 or 
expected to be unstable during the trial. 
29. Have a corrected visual acuity worse than or equal to logarithm of the minimum angle 
of resolution (logMAR), +0.7 as assessed by Early Treatment of Diabetic Retinopathy 
Study (ETDRS) scale in both eyes at Visit 0 and Visit 1.  
30. Have a condition or be in a situation (including language barrier) which the investigator 
feels may put the subject at significant risk, may confound the trial results, or may 
interfere significantly with the subject’s participation in the trial. 
31. Have a history of isotretinoin (e.g. Accutane, Myorisan, Claravis, Amnesteem) use. 
 


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5.5 Re-Screen Procedures  
If the subject does not qualify at Visit 0 or Visit 1, he or she may be re-screened once after 
14 days from the relevant visit provided that new informed consent is signed, new subject 
number is received via IRS and all the assessments are repeated as per protocol 
requirements. 
 
5.6 Subject/Trial Withdrawal Criteria  
Subjects are free to discontinue their participation in the trial at any time without giving 
their reasons. 
A subject must be discontinued after randomization from the trial for any of the 
following reasons:  
• Occurrence of pregnancy; 
• Withdrawal of subject`s consent; 
• Emergency unblinding has occurred. 
A subject must be discontinued from treatment after randomization for any of the 
following reasons (but may remain in the trial for follow up assessments): 
• If at any time during the trial the investigator determines that a subject’s safety has 
been compromised; 
• Occurrence of an exclusion criterion that is clinically relevant and affects the 
subject’s safety;  
• If discontinuation is considered necessary by the investigator and/or sponsor; 
• Occurrence of Adverse Events (AEs) that present an unacceptable consequence or 
risk to the subject in the judgment of the investigator, sponsor, or the medical 
monitor; or is intolerable to the subject.  
 
If a subject has failed to attend scheduled trial assessments, the investigator must determine 
the reasons and the circumstances as completely and accurately as possible. 
In case a subject has to be withdrawn from the trial for safety reasons related to study drug, 
the sponsor will be informed immediately. If there is a medical reason for withdrawal, the 
subject will remain under the supervision of the investigator until satisfactory health has 
returned or the subject´s health has reached a stable condition.  
Subjects who are withdrawn from the trial after dosing will not be replaced.  
In case of premature withdrawal from the trial, the process outlined in Section 8.4.2 should 
be followed. In any case, the appropriate electronic Case Report Form (eCRF) section 
including the reason for discontinuation as defined in Section 8.6.2 must be completed. 


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The trial can be prematurely discontinued as described in Section 8.7. 
6 TRIAL PARAMETERS 
6.1 Efficacy Endpoints 
6.1.1 Primary Efficacy Endpoints: 
Two primary endpoints will be tested in the following order using hierarchical fixed 
sequence testing: 
 
1. Change from baseline (CFB) in total Corneal Fluorescein Staining (tCFS) (NEI scale) 
at Day 57 
2. CFB of Dryness Score (visual analogue scale [VAS] Severity of Dryness) at Day 57 
 
6.1.2 Secondary Efficacy Endpoints: 
The following secondary efficacy endpoints will be evaluated in the following order using 
hierarchical fixed sequence testing: 
 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
 
6.1.3 Other Pre-specified Efficacy Endpoints: 
1. CFB of Dryness Score (VAS) at Day 29  
2. CFB in tCFS at Day 29  
3. CFB in CFS central and inferior sub-regions (NEI scale) to each measured post-baseline 
visit. 
4. Proportion of tCFS responders (≥3 improvement based on NEI scale) at Day 57. 
5. Proportion of Dryness Score responders (≥30 % improvement from baseline) at Day 57. 
6. CFB in VAS burning/stinging, sticky feeling, foreign body sensation, itching, blurred 
vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye 
symptoms at each measured post-baseline visit. 
7. CFB in Ocular Surface Disease Index (OSDI©) at each measured post-baseline visit. 
 
 
 
 
 
  
 
 
 
 
 


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6.2 Safety Endpoints 
1. Ocular and non-ocular TEAEs 
2. Visual acuity 
3. Slit-Lamp biomicroscopy 
4. Intraocular pressure 
5. Dilated fundoscopy 
 
 
 
 
 
 
 
 
 
 


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7 TRIAL MATERIALS 
7.1 Investigational Medicinal Product(s) 
7.1.1 IMP(s)/ Formulation (s) 
NOV03 drug product is a thin, clear, preservative-free ophthalmic solution drop (see Table 
1). Saline eye drops preserved with benzalkonium chloride will be supplied as the control 
product (see Table 2). Investigational drug and control will be provided in identical bottles 
and labels to ensure the double-masked character of the trial. 
 
Table 1 
Active Investigational Product 
 
Investigational Product 
Product code: 
NOV03 
Chemical name: 
Perfluorohexyloctane  
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 
 
 
 
Table 2 
Control Investigational Product 
 
Control Investigational Product 
Product name: 
Saline solution 
Chemical name: 
Sodium chloride solution (0.6 %) 
Molecular formula: 
NaCl 
Dosage form: 
3 mL ophthalmic solution 
Unit dose: 
35-40 µL drop size 
Route of administration: 
Topical ocular administration 
Physical description: 
Colorless and clear ophthalmic solution 
Excipients: 
0.01% benzalkonium chloride w/v 
 
 
 
 
7.1.2 Labeling and Packaging of IMP 
IMP will be labelled according to the legal requirements and packaged into individual 
subject kits, each containing 2 bottles of NOV03 or saline solution. See Section 7.1.4 for 
details regarding dispensation to subjects. 


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In compliance with the Code of Federal Regulations 21 part 312, section 312.6, the labels 
for the IMP shall be comprised of: 
 
• Protocol number 
• Kit Number 
• Investigational new drug statement 
• Storage conditions 
• Name and address of the sponsor 
 
7.1.3 IMP Storage 
The IMPs must be stored in a secure area accessible only to the investigator or pharmacist 
and his/her designees. IMPs must be stored at room temperature under temperature-
monitored conditions and must not be refrigerated. Subjects should be instructed to store 
IMP at room temperature and out of children’s reach at home. Subjects should not use a 
dispensed bottle that has been opened for more than 30 days.  
 
7.1.4 IMP Dispensation 
• The dedicated dosing coordinator is responsible for dispensing the IMP and 
supervision of first dose administration at Visit 1. 
• The IMPs must only be distributed to subjects properly qualified under this protocol to 
receive IMP. 
• IMP will be provided to the clinical sites as subject kits containing 2 bottles of NOV03 
or saline solution. 
• At the end of Visit 1, qualified subjects will be randomized and a kit of IMP containing 
2 bottles for each subject will be assigned using IRS. The first dose of IMP will be 
administered at the clinical site.  
• At Visits 1 and 2 the subject will receive one subject kit.  
• At Visit 3 the subject will receive two subject kits. 
• At Visits 2, 3 and 4 used/unused IMP will be collected from subjects for drug 
accountability by the dedicated dosing coordinator.  
Subjects will be instructed to immediately contact the site if there is any problem with the 
IMP, e.g. kit/bottle(s) was damaged or lost or if the open bottle was dropped. In case the 
subject needs a replacement bottle of IMP, the next bottle from the kit can be used by the 
subject. If no bottle remains in the kit, a new kit will be assigned to the subject using IRS.  
 
7.1.5 Instructions for Use and Administration 
At Visit 1 subjects will be instructed by the dedicated dosing coordinator on appropriate 
hygiene and eye drop dosing technique. Subjects will self-administer NOV03 or saline eye 


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drops in each lower cul-de-sac of each eye as shown in Appendix 2 under the supervision 
of the dedicated dosing coordinator on Day 1 (Visit 1).  
 
Subsequent eye drops on Day 1 are to be instilled by the subjects according to detailed 
written instructions. Subjects will be instructed to instill their drops into both eyes QID for 
the duration of the trial. Clinic staff will coach the subjects to dose themselves at 
approximately the same time every day e.g., morning, lunch time/mid-day, afternoon/early 
evening, and at bedtime. If a dose is missed, then the next dose should be administered on 
time. 
The dedicated dosing coordinator will inform subjects on how to store IMP (see Section 
7.1.3) and dose IMP and how to complete their dosing diary. 
 
Dosing should be continued until the day of the next Visit (should be at least 2 hours before 
first ophthalmic examination).  
 
The bottles are designed for multiple use. Subjects will be instructed to only open one bottle 
at a time. They should be instructed not to discard the empty bottles but keep them in the 
kit box and return them at their next visit in the kit box. Subjects will record dosing in their 
dosing diary. Subjects will be instructed not to show the assigned IMP to the Investigator 
or site staff other than the dedicated dosing coordinator, unless instructed to do so. 
 
7.2 IMP Accountability 
The dedicated dosing coordinator at each site must keep an accurate accounting of IMPs 
received from the supplier by maintaining a detailed inventory. IMP shipment records will 
be verified and accountability performed by comparing the IMP shipment inventory sheet 
to the actual quantity of used/unused IMP bottles received at the site.  
 
Accurate records of receipt and disposition of the IMP (e.g. dates, quantity, subject number, 
kits used, kits unused, etc.) must be maintained by the dedicated dosing coordinator at each 
site. This includes the amount dispensed to subjects, amount returned to the site by the 
subjects, and the amount returned to the sponsor or designee upon completion of the trial.  
 
Investigational trial medication orders, records of receipts, dispensing records, and 
inventory forms will be examined and reconciled by the dedicated dosing coordinator. At 
each visit, subjects will return all bottles to clinic staff for accountability purposes. 
Accountability will be ascertained by performing reconciliation between the amount of IMP 
cartons (kits and their components) sent to the site, the amount used and unused at the time 
of reconciliation. All investigational trial medication that is dispensed during the course of 
the trial must be accounted for on an IMP accountability form. No IMP kits or bottles will 
be returned to the sponsor prior to full accountability by sponsor’s monitor. 


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7.3 IMP Handling and Return  
Unless otherwise directed, at the end of the trial all returned (used and unused) IMP must 
be directly shipped from the clinical site to the sponsor for destruction of the medications. 
Note: The medications should not be disposed or returned prior to full accountability 
by the sponsor’s monitor. The clinical site will include a copy of all completed drug 
disposition forms with the IMP to the sponsor after full accountability is completed. 
 
7.4 IMP Masking  
Investigational drug and control will be provided in identical bottles and labels to ensure 
the double-masked character of the trial. The Investigator/site staff and Bausch & Lomb, 
Incorporated. personnel or designee(s) involved in the conduct of the trial will be masked 
to the IMP. Clinical Trial Material Supply Chain are unmasked designee. 
 
Due to physicochemical differences between NOV03 and saline, there will be a dedicated 
dosing coordinator who will be responsible for the handling of IMP and activities (such as 
dispensation, collection, accountability) surrounding the use of IMP.  
 
Each site must have a dedicated dosing coordinator that will be responsible for: 
• all IMP dispensation and accountability,  
• daily diary dosing education/review,  
• all discussions with study subjects related to IMP,  
• the administration of the Eyedrop Acceptability and Instillation Comfort 
Questionnaires.  
 
This designee shall not participate in any other trial procedures and not report this 
information to other staff. Subjects will be instructed to administer the IMP out of the sight 
of the Investigator or site staff other than the dedicated dosing coordinator. Subjects are not 
to show or discuss the properties of the assigned IMP to the Investigator or site staff other 
than the dedicated dosing coordinator, unless instructed to do so. 
 
7.5 Other Trial Supplies 
Diaries, Questionnaires, Urine Pregnancy Tests, Meibomian Gland Evaluator stick, 
Schirmer’s test strips, sodium fluorescein, will be provided to sites. Respective instructions 
are available in Appendix 3 and manual of operations. 


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8 TRIAL METHODS AND PROCEDURES 
8.1 Concurrent Medications and 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 or previous medications are to be recorded for 60 days 
prior to Visit 0. Any physical therapies, or surgeries are to be documented for 6 months 
prior to Visit 0. 
Therapy considered necessary for the subject’s welfare that will not interfere with the 
evaluation of the study medication may be given at the discretion of the Investigator and in 
consultation with the medical monitor. If there is any question as to whether the medication 
may interfere, the investigator should contact the medical monitor or sponsor. Whenever 
possible, medications should be administered in dosages that remain constant throughout 
the study duration. 
Physical therapies such as lid scrubs, lid wipes, warm compresses, systemic antibiotics 
(such as tetracyclines) and oral supplements for treatment of ocular conditions must be 
stable within the last 30 days prior to Visit 1 and should be maintained stable throughout 
the trial. Changes in those therapies or initiation of such therapies should be recorded on 
the subject’s source document and corresponding eCRF. 
8.2 Prohibited Medications 
Disallowed medications and treatments are listed in the exclusion criteria (Section 5.4). All 
medications and treatments that were not allowed prior to trial are also not allowed during 
the trial in particular wearing of contact lenses, ocular surgery/ocular laser treatment of any 
kind, and no other dry eye treatments such as artificial tears, gels, or ointments or 
TrueTearTM device (Intranasal Tear Neurostimulator) shall be used within 24 hours prior to 
Visit 1 and throughout the course of the trial.  
 
Specific prohibitions: 
• Topical ocular steroid treatments, topical cyclosporine, lifitegrast, serum tears or 
topical anti-glaucoma medication within 60 days prior to Visit 0 and during the trial. 
• Oral medications known to cause ocular drying (e.g., antihistamines, 
antidepressants, etc.) on a non-stable regimen within 1 month prior to Visit 0 or 
expected to be unstable during the trial. Amitriptyline (e.g., Elavil) is only allowed 
as sleep aid and should not be used within 24 hours prior to any visit (see Section 
8.1). 
• History of isotretinoin use  
 
Concurrent enrollment in another investigational drug or medical device trial is not 
permitted. 


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8.4 Examination Procedures 
8.4.1 Procedures to be performed at each trial visit with regard to trial objective(s) 
See Appendix 1 for a schedule of visits and measurements in recommended order. 
Appendix 3 describes the eye examinations. These should not be done earlier than 2 hours 
after IMP instillation. If possible the same investigator/coordinator should perform the 
assessments for an individual subject. Primary endpoint assessments at Baseline Visit 1 
(Day 1) and Visit 4 (Day 57) should be done preferably on the same time of the day. 
The dedicated dosing coordinator will perform tasks as described in Section 7.4. 
 
Visit 0 (Up to 14 days before Visit 1): Screening 
• Informed consent / HIPAA; 
• Demographic data and medical / medication history; 
• Review of inclusion / exclusion criteria;  
• Urine pregnancy test; 
• 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 start of 
Schirmer`s test);  
• Schirmer’s test I (without anesthesia); 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Non-leading AE questioning (Adverse event query); 
• Qualified subjects will be scheduled for Visit 1. 


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Visit 1 (Day 1): Baseline/Randomization 
• Previous/Concomitant Medication; 
• Review of inclusion / exclusion criteria; 
• Urine pregnancy test; 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of 
dry eye symptoms; 
• 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 before start of 
Schirmer`s test); 
• Schirmer’s test I (without anesthesia); 
• Randomization; 
• In-office dose of IMP; 
• Instillation comfort questionnaire; 
• Non-leading AE questioning (Adverse event query); 
• Dispensation of dosing diary; 
• Drug dispensation of one kit for self-administered dosing until Visit 2; 
o Subjects will be instructed on how to administer IMP; 
o Subjects will be instructed to dose with IMP on the day of their next visit at 
least 2 hours before the start of their visit (Visit 2); 
o Subjects will be instructed on how to complete the dosing diary. 
 
Visit 2 (Day 15 ± 1), Visit 3 (Day 29 ± 2):  
• At the beginning of the visit the subject will be asked about the time of last dose. 
Assessments should be performed at least 2 hours after last dose of IMP; 
• Collection and review of IMP and dosing diary; 
o Calculate subject compliance with doses in the subject diary as described 
in Section 8.5 and re-educate subject as necessary.  
• Concomitant medication update; 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of 
dry eye symptoms; 
• Ocular Surface Disease Index (OSDI©) questionnaire;  
• Visual acuity (ETDRS); 
• Slit-Lamp biomicroscopy; 
• Fluorescein staining (NEI scale); 
• Non-leading AE questioning (Adverse event query); 
• Re-dispensation of dosing diary;  


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Visit 2 Drug dispensation of one kit for self-administered dosing until Visit 3; 
o Subjects will be instructed on how to administer IMP; 
o Subjects will be instructed to dose with IMP on the day of their next visit 
at least 2 hours before the start of their visit (Visit 3); 
o Subjects will be instructed on how to complete the dosing diary. 
Visit 3 Drug dispensation of two kits for self-administered dosing until Visit 4; 
o Subjects will be instructed on how to administer IMP; 
o Subjects will be instructed to dose with IMP on the day of their next visit 
at least 2 hours before the start of their visit (Visit 4); 
o Subjects will be instructed on how to complete the dosing diary. 
 
Visit 4 (Day 57 ± 2) or ET: 
• At the beginning of the visit the subject will be asked about the time of last dose. 
Assessments should be performed at least 2 hours after last dose of IMP; 
• Collection and review of IMP and diary; 
• Concomitant medication update; 
• Urine pregnancy test; 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of 
dry eye symptoms; 
• Ocular Surface Disease Index (OSDI©) questionnaire; 
• Eyedrop acceptability 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 before start of 
Schirmer`s test);  
• Schirmer’s test I (without anesthesia); 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Non-leading AE questioning (Adverse event query); 
• Trial exit. 
 
8.4.2 Early Termination/Discontinuation 
The following data from subjects discontinuing before randomization (i.e. screen failures) 
will be captured in the eCRF: 
• Demographics 
• AEs / SAEs 
• Reason for discontinuation (including applicable assessment results) 
 
If a randomized subject is discontinued from the trial prior to Visit 4 (Day 57 ± 2) and not 
willing to perform all subsequent visits and assessments, then all evaluations planned for 


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Visit 4 should be performed on the day of discontinuation (early termination) or at the 
discretion of the investigator. 
Randomized and dosed subjects who discontinue treatment for any reason will be 
encouraged to undergo all subsequent trial visits and assessments. 
Data from subjects discontinuing after randomization will be captured completely in the 
eCRF including Early Termination Visit and reason for discontinuation. 
 
8.4.3 Unscheduled Visits 
An unscheduled visit may be performed during the course of the trial in order to ensure 
subject safety and/or to dispense additional IMP if necessary (i.e. damaged/lost or subject 
ran out of IMP in between visits). All procedures performed at an unscheduled visit will be 
recorded in the source documents and on the unscheduled visit eCRF pages. Any 
unscheduled visit procedure listed in the eCRF that is not performed should be indicated as 
“not done.” 
 
Evaluations that may be conducted at an unscheduled visit include: 
• Slit-Lamp biomicroscopy; 
• Visual acuity; 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Urine pregnancy test (for women of childbearing potential); 
• Assessment of AEs; 
• Assessment of concomitant medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 
 
8.5 Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of IMP at Visits 1, 2, and 3, 
and provided with written instructions (see Appendix 2). The used and unused IMP bottles 
will be collected from subjects at Visits 2, 3 and 4 to assess subject dosing compliance.  
 
Subject dosing compliance will be determined by the subject’s response or lack thereof to 
the prompt “Was the dose taken?” in the subject diary. If more than 20% of the responses 
to the total expected dose-taken prompts are checked “no,” left blank, or missing, then the 
subject will be deemed noncompliant for dosing and a deviation recorded e.g., 12 checked 
“no,” left blank, or missing at Visit 2 and Visit 3 and more than 24 at Visit 4. 
 
8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the trial. 


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8.6.2 Discontinued subjects 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to the CRO and/or trial sponsor and will be clearly documented in the eCRF as: 
• Adverse event; 
• Protocol violation; 
• Lack of efficacy; 
• Administrative reason (e.g. inability to continue, lost to follow up); 
• Sponsor termination of trial; 
• Subject choice (e.g. withdrawal of consent);  
• Other 
Subjects must be discontinued as outlined in Section 5.6. 
Subjects who discontinue for any reason after randomization will not be replaced. 
 
8.7 Trial Termination 
The whole trial may be discontinued prematurely in the event of any of the following:  
• New information leading to unfavorable risk-benefit judgment of the IMP, e.g. 
due to: 
o Occurrence of significant previously unknown adverse reactions or 
unexpectedly high intensity or incidence of known adverse reactions, or 
o Other unfavorable safety findings. 
• Sponsor’s decision that continuation of the trial is unjustifiable for medical or 
ethical reasons. 
• Poor enrollment of subjects making completion of the trial within an 
acceptable time frame unlikely. 
• Discontinuation of development of the sponsor’s IMP. 
• Terminated or suspended upon request of Health Authorities. 
 
Health Authorities and Institutional Review Boards (IRBs)/ Independent Ethics 
Committees (IECs) will be informed about the discontinuation of the trial in accordance 
with applicable regulations. 
 
8.8 Trial Duration 
An individual subject’s participation will involve 5 visits over approximately a 10-week 
period, including screening. After the trial, subjects will be treated according to standard of 
care, at the discretion of the treating physician. The total duration of the trial from “first 
subject in” to “last subject out” is expected to be 7 months. 
 


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9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related. An AE can 
therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease occurring after the subject signature of the ICF without any judgment 
on causality. 
 
If there is a worsening of a medical condition that was present prior to Visit 0, this should 
also be considered a new AE and reported. Any medical condition present prior to the 
administration of the IMP that remains unchanged or improved should not be recorded as 
an AE at subsequent visits. 
 
Worsening of DED will be considered an AE only if the dry eye status of the subject 
exceeds their previous experiences with the condition. This will be determined by the 
subject and the investigator. 
 
A clinically significant visual acuity worsening (defined as an increase of 0.22 or greater in 
logMAR score) from screening (Visit 0) will be considered an Adverse Event. 
 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IMP, expectedness, action(s) taken, seriousness, and outcome of 
any sign or symptom observed by the physician or reported by the subject upon non-leading 
AE questioning. 
 
AEs (both elicited and observed) and SAEs will be monitored throughout the trial. The 
investigator will promptly review all AEs for accuracy and completeness. All AEs will be 
documented on the appropriate source document and eCRF. 
 
Adverse events recorded from the signing of informed consent through the last study visit 
must be reported, regardless of whether or not the AEs are considered study-related. 
 
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 IMP 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. 
 


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9.1.2 Relationship to Investigational Product 
The relationship of each AE to the investigational drug should be determined by the 
investigator using these explanations: 
• Suspected: A reasonable possibility exists that the investigational product 
caused the AE.  
• Not Suspected: A reasonable possibility does not exist that the investigational 
product caused the AE.  
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the investigational product caused the AE. “Reasonable possibility” means there is 
evidence to suggest a causal relationship between the investigational product and the AE. 
Types of evidence that would suggest a causal relationship between the investigational 
product and the AE include: a single occurrence of an event that is uncommon and known 
to be strongly associated with IMP exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome); one or more occurrences of an event that is not commonly associated 
with IMP exposure, but is otherwise uncommon in the population exposed to the IMP (e.g., 
tendon rupture); an aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the trial population independent of drug therapy) that 
indicates those events occur more frequently in the IMP-treatment group than in a 
concurrent or historical control group. 
 
9.1.3 Expectedness 
The expectedness of a treatment emergent AE should be determined based upon existing 
safety information about the IMP. The active ingredient of NOV03 is perfluorohexyloctane, 
which is a semifluorinated alkane with a well-established tolerability and safety profile. It 
has been tested in four PMCF studies and one phase 2 clinical trial up to now with >370 
subjects that received NOV03 treatment. AEs of those studies have been listed in the 
Investigator’s Brochure. Therefore, the following definitions will be used: 
 
• Unexpected: An AE that is not listed in the investigator’s brochure in the Adverse 
Reaction Section at the specificity or severity that has been observed. 
• Expected: An AE that is listed in the investigator’s brochure in the Adverse 
Reaction Section at the specificity and severity that has been observed. 
• Not Applicable: Any AE with an onset prior to first dose of IMP. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the sponsor’s determination. 
 
9.1.4 Outcome 
The outcome of any AE will be determined and recorded using the following categories: 
 
• Recovered/Resolved 
• Recovering/Resolving 


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• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Lost to Follow-up 
• Fatal 
• Unknown 
 
9.2 Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator, medical monitor or 
sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
o Note:  An AE is considered “life-threatening” if, in the view of either the 
investigator, medical monitor 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; 
o Note:  The term “inpatient hospitalization” refers to any inpatient admission (even 
if less than 24 hours). For chronic or long-term inpatients, inpatient admission 
includes transfer within the hospital to an acute/intensive care inpatient unit. 
Inpatient hospitalization does not include: emergency room visits; outpatient/same-
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
o 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; 
o Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g. 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
• A congenital anomaly/birth defect; 
• Medically important 
o 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. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 


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9.3 Procedures for Reporting Serious Adverse Events 
All AEs and their outcomes must be reported to CRO, the trial sponsor, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate source document and eCRF page. 
 
9.3.1 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IMP, must be 
immediately (i.e. within a maximum 24 HOURS after becoming aware of the event) 
reported to CRO. All information relevant to the SAE must be recorded on the appropriate 
SAE report form. Within 24 hours of knowledge of a new SAE, the investigator must enter 
the SAE information onto the hard copy SAE report form and send the form to the 
 
 The investigator must verify that the report was received by 
CRO. If the investigator is not able to verify it was successfully received by CRO, the 
investigator must call the CRO clinical study manager by phone to follow-up. The CRO 
will forward the documentation to the medical monitor and the sponsor for review. 
 
The information entered must contain sufficient information to enable medical assessment 
by the medical monitor. At a minimum, the initial SAE report should contain the following 
information: 
 
● Subject’s trial ID number 
● Description of the Serious Adverse Event 
● Date of the Serious Adverse Event  
● Criterion for seriousness 
● Preliminary assignment of causality to IMP 
 
All information relevant to the SAE must be recorded on the appropriate case report forms. 
The investigator is obligated to pursue and obtain information requested by CRO, CRO 
and/or the sponsor in addition to that information reported on the case report form. All 
subjects experiencing a SAE must be followed up and the outcome must be reported. 
The investigator must 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 CRO and the trial 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 IMP; and inform the IRB of the AE within their guidelines for reporting 
SAEs. 
 
All SAEs will be reported from the signature of Informed Consent until 30 days after the 
last administration of study drug. 
 
All SAEs will be followed until resolution, stabilization, the event is otherwise, explained, 
or the subject is lost to follow-up. 
 


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Investigators are not obligated to actively seek SAE information from subjects that 
completed the study, but investigators are encouraged to notify the Sponsor, or designee, 
of any SAEs of which they become aware occurring at any time after a subject has 
discontinued or completed the study that they judge may be reasonably related to treatment 
with study drug. 
 
9.3.2 Reporting a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
All SAEs that are ‘suspected’ and ‘unexpected’ are to be reported to CRO within 24 hours 
after the site becomes aware of the event, via the SAE reporting process outlined above. All 
SAE/SUSARs will be promptly reported to the IRB/IEC and governing health authorities 
(e.g., United States Food and Drug Administration [FDA]) as required by the IRB/IEC, 
federal, state, and local regulations and timelines. 
 
9.4 Procedures for Unmasking of IMP 
All subjects, investigators, and trial personnel involved with the conduct of the trial will be 
masked with regard to treatment assignments. The mask may be broken in exceptional 
circumstances.  
In a medical emergency, when the management of a subject’s condition requires knowledge 
of the treatment assignment, the investigator, or designee, will obtain the trial treatment 
assignment from the Interactive Response System (IRS). If possible, the medical 
emergency should be discussed with the medical monitor prior to obtaining the treatment 
assignment, or as soon after as possible. The sponsor may unmask for regulatory submission 
determination of an SAE when necessary (see Section 9.3.1). 
In a non-emergency situation, when a code break is required, it must be discussed with the 
medical monitor and/or CRO and the trial sponsor. The code break must be approved in 
writing by the sponsor. 
If the randomization code for a subject is broken, the investigator will record the date and 
reason for lifting the mask for that subject in the source documents. Upon unmasking, the 
subject will be withdrawn from the trial and should complete both the Early Termination 
and Follow-up procedures. 
 
9.5 Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to follow-
up or until the AE is otherwise classified. Resolution means the subject has returned to 
baseline state of health or the investigator does not expect any further improvement or 
worsening of the AE. If the subject is lost to follow-up, the investigator should make 3 
reasonable attempts to contact the subject via telephone, post, or certified mail. All follow-
up will be documented in the subject’s source document. Non-serious AEs identified on the 
last scheduled contact must be recorded on the AE eCRF with the status noted.  
 


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If the investigator becomes aware of any new information regarding an existing SAE (i.e. 
resolution, change in condition, or new treatment), a new SAE Report Form must be 
completed and faxed to CRO within 24 hours of the site’s awareness of the new 
information. The original SAE form is not to be altered, but a new SAE Report Form must 
be completed and identified consecutively based on the previous report form (i.e. Initial 
Report, Follow-up #1, Follow-up #2, etc.). The report must describe whether the event has 
resolved or continues and how the event was treated. 
 
9.6 Reporting Pregnancies 
Pregnancy itself is not considered an AE or SAE (unless there is a suspicion that the IMP 
may have interfered with the effectiveness of a contraceptive medication). Pregnancy is an 
important medical event that must be followed up. Any pregnancy that occurs during the 
clinical trial where the fetus could have been exposed to IMP must be followed through the 
outcome of the pregnancy.  
 
It is the responsibility of the Investigator to obtain the outcome and condition of the infant 
information within 30 calendar days after the initial notification and approximately 30 
calendar days postpartum. 
 
If a subject or investigator suspects that the subject may be pregnant prior to IMP 
administration, the IMP must be withheld until the results of pregnancy testing are 
available. If pregnancy is confirmed, the subject must not receive IMP and must not be 
enrolled in the trial. If pregnancy is suspected while the subject is receiving IMP treatment, 
the IMP must immediately be withheld until the result of pregnancy testing is known. 
 
If a female reports a pregnancy or has a positive pregnancy test during the trial, then the 
investigator must report the pregnancy and the outcome of the pregnancy to the CRO within 
24 hours of learning about the pregnancy and outcome of the pregnancy respectively. 
 
A Pregnancy Report Form will be completed by the trial site’s principal investigator and 
and send the form to the 
. The investigator must verify 
the report was received by CRO. If the investigator is not able to verify it was successfully 
received by CRO, the investigator must call the CRO clinical study manager by phone to 
follow-up. The CRO will forward the documentation to the medical monitor and the 
sponsor for review. 
 
At the completion of the pregnancy, the Pregnancy Report Form is to be submitted to the 
CRO via the SAE contact details.  
 
 


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10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
The following analysis populations will be considered: 
 
Full Analysis Set (FAS) – The FAS includes all randomized subjects who received at least 
one dose of investigational product. The primary analysis will be performed on the FAS. 
Subjects in the FAS will be analyzed as randomized. 
 
Per Protocol Set (PPS) – The PPS includes subjects in the FAS who do not have significant 
protocol deviations and who complete the study. Protocol deviations will be assessed prior 
to database lock and unmasking. The PPS will be analyzed using observed data only for 
efficacy variables. Subjects in the PPS will be analyzed as treated. 
 
Safety Set (SAF) – The SAF includes all randomized subjects who have received at least 
one dose of the investigational product. The SAF will be analyzed for all safety 
assessments. Subjects in the SAF will be analyzed as treated.  
 
The statistical analysis of safety data will be performed for the SAF. The analysis of 
baseline and efficacy data will be performed for the FAS. The primary efficacy analyses 
will also be performed on the PPS as sensitivity analyses. 
 
10.2 Statistical Hypotheses 
The primary endpoints will be tested in a hierarchical fixed sequence in the following order. 
 
The statistical hypotheses for the primary endpoint of CFB corneal fluorescein staining 
(NEI scale) total score at Day 57 are as follows: 
 
H01: 
The difference, between study eyes treated with NOV03 and study eyes 
treated with saline, in the mean CFB corneal fluorescein staining (NEI scale) 
total score at Day 57 = 0. 
 
HA1:  The difference, between study eyes treated with NOV03 and study eyes 
treated with saline, in the mean CFB corneal fluorescein staining (NEI scale) 
total score at Day 57 ≠ 0, with superiority claimed if the difference is less 
than 0 (NOV03 minus saline). 
 
The statistical hypotheses for the hierarchical primary endpoint of the CFB Dryness Score 
at Day 57 are as follows: 
 
H02: 
The difference, between subjects treated with NOV03 and subjects treated 
with saline, in the mean CFB Dryness Score at Day 57= 0. 
 
HA2:  The difference, between subjects treated with NOV03 and subjects treated  


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with saline, in the mean CFB Dryness Score at Day 57 ≠ 0, with superiority 
claimed if the difference is less than 0 (NOV03 minus saline). 
 
Hierarchical fixed sequence testing will be employed to maintain the type I error rate within 
the two primary endpoints. The primary analyses will first test the difference in the mean 
CFB corneal fluorescein staining (NEI scale) total score between treatments at Day 57. If 
the test of the difference is statistically significant at the two-sided alpha = 0.05 level in 
favor of NOV03 then the trial will be considered a success; NOV03 will be declared to be 
superior to saline in the mean CFB corneal fluorescein staining (NEI scale) total score at 
Day 57; and the difference in the mean CFB total Dryness Score between treatments at Day 
57 will be tested at the two-sided alpha = 0.05 level. 
 
If in addition to a statistically significant test of the difference in the mean CFB corneal 
fluorescein staining (NEI scale) total score at Day 57 is in favor of NOV03, and the test of 
the difference in the mean change from Dryness Score at Day 57 is also statistically 
significant in favor of NOV03, then NOV03 will be declared to be superior to saline in both 
the mean CFB corneal fluorescein staining (NEI scale) total score and the mean CFB of the 
Dryness Score at Day 57. 
 
10.3  Sample Size 
 
 
 
 
 
The study has been designed to have at least 95% power to reject both H01 and H02 assuming 
independence between the sign and symptom endpoint; positive correlation between these 
two endpoints would increase the overall power.  
Two hundred fifty (250) subjects (study eyes) per treatment group yields 97.9% power to 
reject H01 in favor of HA1 and conclude superiority of NOV03 over saline in the mean CFB 
tCFS score at Day 57 assuming a true difference (NOV03 minus saline) of -1.0, a common 
standard deviation of 2.8, and a two-sided alpha = 0.05. Two hundred fifty (250) subjects 
per treatment group yields 97.9% power to reject H02 in favor of HA2 and conclude 
superiority of NOV03 over saline in the mean CFB Dryness Score (VAS) at Day 57 
assuming a true difference (NOV03 minus saline) of -10, a common standard deviation of 
28, and a two-sided alpha = 0.05. Accounting for an assumed 10% subject discontinuation 
rate, approximately 560 subjects (280 subject each arm) will be randomly assigned to trial 
treatment such that approximately 250 evaluable participants per arm complete the trial. 
 


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Therefore, assuming independence between tCFS score and Dryness Score (VAS), 250 
FAS subjects per treatment group at Day 57 yields 97.9%* 97.9%= 95.8% power to reject 
both H01 and H02. 
 
10.4 Statistical Analysis 
10.4.1 General Considerations 
Quantitative variables will be summarized using number of subjects (n), mean, median, 
standard deviation, minimum and maximum. The qualitative variables will be summarized 
using counts and percentages.  
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and AEs will be 
coded to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline measures are defined as the last non-missing measure prior to the initiation of 
randomized study treatment. 
All primary and secondary analyses will be two-sided at a significance level of 0.05. 
 
10.4.2 Unit of Analysis 
For efficacy endpoints, the unit of analysis will be the study eye as defined by the following: 
Study Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria. In the case 
that both eyes are eligible for analysis, the worst eye shall be chosen, and this will be defined 
as the eye with worse (higher) total corneal staining at Visit 1. If the total corneal staining 
is the same in both eyes then the right eye will be selected as the study eye. 
 
10.4.3 Missing Data 
The primary analysis will be completed on the FAS with available data per subject, 
assuming the overall study discontinuation rate is <5%.  If the overall study 
discontinuation rate is ≥5% then the primary analysis will be based on the primary 
imputation methodology as defined Section 10.4.5 and the available data analyses will 
become robustness analyses. 
Additionally, robustness analyses will include repeating the primary analysis on the per 
protocol set (PPS); the FAS imputing missing data using last observation carried forward 
(LOCF); the FAS imputing missing data using Markov Chain Monte Carlo (MCMC) 
multiple imputation methodology under different assumptions of missingness (at random 
and not at random) each using 30 imputed values. 
 
The imputation model, for each visit, under the assumption of missing at random is: 
 
PROC MI DATA=INDATA SEED=97656 OUT=OUTDATA1 MINIMUM = 0 MAXIMUM = 3 ROUND 
= 1 NIMPUTE=30; 
  MCMC INITIAL=EM; 
  BY <TREATMENT>; 


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  VAR <BASELINE> <PARAMETER>; 
RUN; 
where PARAMETER has 5 levels and refers to the corneal fluorescein staining 
score for each region (inferior, superior, central, temporal, and nasal). 
The imputation model, for each visit, under the assumption of missing not at 
random is: 
PROC MI DATA=INDATA SEED=36797 OUT=MDATA MINIMUM = 0 MAXIMUM = 3 ROUND = 
1 NIMPUTE=30; 
  MCMC IMPUTE=MONOTONE; 
  VAR <BASELINE> <PARAMETER>; 
RUN; 
 
PROC MI DATA=MDATA SEED=38549 OUT=OUTDATA2 MINIMUM = . 0 0  
 
MAXIMUM = . 3 3 ROUND = . 1 1; 
  CLASS <TREATMENT>; 
  MONOTONE REG(<PARAMETER> = <BASELINE> / DETAILS); 
  MNAR MODEL(<PARAMETER> / MODELOBS=(<TREATMENT>=’Saline’)); 
  VAR <TREATMENT> <BASELINE> <PARAMETER>; 
RUN; 
 
where PARAMETER has 5 levels and refers to the corneal fluorescein staining score for 
each region (inferior, superior, central, temporal, and nasal). 
 
10.4.4 Multiplicity Consideration 
To control for inflation of type 1 error rate due to multiple hypotheses, the analysis of the 
two primary endpoints will be conducted in a hierarchical manner. 
 
If both primary endpoints demonstrate statistically significant superiority of NOV03 versus 
saline at the two-sided alpha = 0.05 level, the following secondary endpoints will be tested 
hierarchically to maintain an overall two-sided alpha = 0.05. 
1. CFB of Dryness Score (VAS) at Day 15 
2. CFB in total Corneal Fluorescein Staining (tCFS) (NEI scale) at Day 15  
3. CFB of VAS burning/stinging at Day 57 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57 
 
10.4.5 Primary Efficacy Analyses 
The primary comparisons in this trial will be between NOV03 versus saline at Day 57 in 
the FAS with available data per subject using the following estimands: 
• Population: Subjects with DED defined through enrollment criteria 
• Endpoint:  
o CFB in tCFS in the study eye at Day 57 
o CFB of Dryness Score (VAS) at Day 57 
• Intercurrent event:  
o Discontinuation of study medications is ignored. [treatment policy strategy] 
o Non-optimal compliance is ignored. [treatment policy strategy] 


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o Withdrawal due to any reason. Missing data not imputed. [hypothetical 
strategy] 
• Population-level summary:  
o Difference in the mean CFB in tCFS in the study eye at Day 57 between 
NOV03 and saline. 
o Difference in the mean CFB of Dryness Score (VAS) at Day 57 between 
NOV03 and saline. 
If the overall study discontinuation rate is ≥5% then the primary analysis will be based on 
imputation methodology using the following estimands and the available data analyses will 
become robustness analyses.:  
• Population: Subjects with DED defined through enrollment criteria 
• Endpoint:  
o CFB in tCFS in the study eye at Day 57 
o CFB of Dryness Score (VAS) at Day 57 
• Intercurrent event:  
o Discontinuation of study medications is ignored. [treatment policy strategy] 
o Non-optimal compliance is ignored. [treatment policy strategy] 
o Withdrawal due to lack of efficacy or adverse events. Baseline observation 
carried forward (BOCF) is used to impute missing data [hypothetical 
strategy]. 
o Missing data without withdrawal or withdrawal due to reasons other than 
lack of efficacy or adverse events. Multiple imputations using randomized 
treatment-based Markov Chain Monte Carlo is used to impute missing data 
[hypothetical strategy]. 
• Population-level summary:  
o Difference in the mean CFB in tCFS in the study eye at Day 57 between 
NOV03 and saline. 
o Difference in the mean CFB in Dryness Score (VAS) at Day 57 between 
NOV03 and saline. 
 
The primary comparison in this trial will be between NOV03 versus saline at Day 57. The 
primary efficacy endpoints (e.g. CFB in total corneal fluorescein staining [NEI scale] and 
Dryness Score) will be tested using hierarchical fixed sequence testing and summarized 
descriptively (n, mean, standard deviation, median, min, and max) and analyzed separately 
using an ANCOVA model with terms for baseline value, and treatment. 
 
Least squares mean for each treatment group and for the difference between treatment 
groups will be presented from each model together with two-sided p-values (used for 
primary inference) and 95% confidence intervals. 
 
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures analysis 
comparing treatment groups will be performed as sensitivity analyses. The mixed-effect 
repeated measures model will include treatment, baseline value, visit, and the interaction 
between treatment and visit as fixed effects, and subject as a random effect. An unstructured 


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covariance matrix will initially be used to model the covariance among repeated measures; 
however, if the model fails to converge using this covariance structure, either heterogeneous 
TOEPLITZ, homogeneous TOEPLITZ, or compound symmetry will be implemented 
according to the Akaike information criterion with a correction for finite sample sizes 
(AICc). 
 
10.4.6  Secondary Efficacy Analyses 
The following secondary endpoints will be tested hierarchically: 
 
1. CFB of Dryness Score (VAS) at Day 15. 
2. CFB in tCFS (NEI scale) at Day 15.  
3. CFB VAS burning/stinging at Day 57. 
4. CFB in central Corneal Fluorescein Staining (cCFS) (NEI scale) at Day 57. 
 
Inference will only be made on these endpoints, at a 2-sided alpha = 0.05, if both primary 
endpoints and any higher order secondary endpoints are statistically significant at a 2-sided 
alpha = 0.05 in favor of NOV03. 
Quantitative secondary efficacy endpoints will be summarized similarly to the primary 
effiacy endpoints. 
The primary analysis of the secondary endpoints will use the FAS with available data per 
subject, assuming the overall study discontinuation rate is <5%. If the overall study 
discontinuation rate is ≥5%, then the primary analysis of the secondary endpoints will be 
based on imputation methodology as defined in Section 10.4.5 and the available data 
analyses will become robustness analyses. 
 
10.4.7 Other Pre-specified Efficacy Analyses 
The analyses of other pre-specified endpoints will use the Full Analysis Set (FAS) with 
available data per subject. 
 
1. CFB of Dryness Score (VAS) at Day 29. 
2. CFB in tCFS at Day 29. 
3. CFB in CFS central and inferior sub-regions (NEI scale) to each measured post-baseline 
visit. 
4. Proportion of tCFS responders (≥3 improvement based on NEI scale) at Day 57. 
5. Proportion of Dryness Score responders (≥30 % improvement from baseline) at Day 57. 
6. CFB in VAS burning/stinging, sticky feeling, foreign body sensation, itching, blurred 
vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye 
symptoms at each measured post-baseline visit. 
7. CFB in Ocular Surface Disease Index (OSDI©) at each measured post-baseline visit. 
Quantitative other pre-specified efficacy endpoints will be summarized descriptively (n, 
mean, standard deviation, median, min and max) by visit, and analyzed similarly to the 
primary endpoint at each measured visit. Least squares mean for each treatment group and 


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for the difference between treatment groups will be presented from the model together with 
two-sided p-values and 95% confidence intervals.  
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures analysis 
will also be presented as sensitivity analyses.  
Other pre-specified endpoints evaluating the proportion of study eyes (or subjects) meeting 
pre-defined criteria will be presented and tested between treatment groups using logistic 
regression analysis adjusting for baseline tCFS score at each measured follow-up visit. 
Pearson chi-squared analysis comparing the treatment groups will be performed as 
sensitivity analyses. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Exploratory and other endpoints will be summarized and analyzed similarly to the other 
pre-specified endpoints. 
 
10.4.10 Safety Variables Analyses 
All safety analyses will be performed on the Safety Population. The primary evaluation of 
safety of the active arm will be against the control arm. 
 
Extent of Exposure 
Dosing information for each treatment and each subject will be listed. Discontinuation of 
treatment will be summarized by treatment received. The primary reason for IMP 
discontinuation will also be summarized by treatment received. 
 
Analysis of Adverse Events 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and 
percentages of subjects with TEAEs, serious TEAEs, and TEAEs causing premature 
discontinuation will be provided by treatment group. An AE is treatment emergent if it 
occurs or worsens after the first dose of trial treatment. Furthermore, frequencies will be 


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given of subjects with TEAEs by system organ class; by system organ class and preferred 
term; by system organ class, preferred term and maximal severity; by system organ class, 
preferred term and strongest relationship; and by system organ class, preferred term, 
maximal severity, and strongest relationship. Separate summaries will be performed for 
ocular and non-ocular AEs.  
 
The treatment groups will be compared in regard to safety endpoints descriptively. No 
inferential comparison will be conducted. 
 
Concomitant Medications 
Concomitant medications will be coded using the most recent version of WHO-Drug 
Dictionary and summarized by treatment group. 
 
Other safety endpoints including those assessed by visual acuity, slit-lamp biomicroscopy, 
dilated fundoscopy, and intraocular pressure will be summarized by treatment group and 
visit using descriptive statistics. Changes from baseline will also be summarized where 
appropriate. For assessments performed by eye, study eye and fellow eye will be 
summarized separately.  
 
10.4.11 Interim Analyses 
No interim analyses are planned for this trial. 
 
10.5 Additional Analyses 
No further analysis is planned. 
 
10.6 Methods to Minimize Bias 
This is a randomized treatment assignment, double-masked, multi-center trial. Subjects will 
be instructed not to show or discuss the properties of the assigned Investigational Medicinal 
Product (IMP) and/or their experience with the IMP with other trial participants, and not to 
show or discuss the IMP with the Investigator or site staff other than the dedicated dosing 
coordinator, unless instructed to do so. 
 
A dedicated dosing coordinator at each site will be responsible for instructing subjects 
regarding IMP handling/administration, IMP dispensation and accountability, reviewing 
daily dosing diaries, performing the Instillation Comfort Questionnaire, the Eyedrop 
Acceptability Questionnaire and all discussions with study subjects related to IMP.  
 
 


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11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This trial will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs), including the International Conference on Harmonization (ICH) Guidelines, and 
in general, consistent with the Declaration of Helsinki. In addition, all applicable local, 
state, and federal requirements relevant to the use of IMPs in the countries involved will be 
adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent must take place before any trial specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject prior to enrollment 
into the trial. 
 
All informed consent forms must first be approved by the sponsor and receive approval 
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 
the governing IRB/IEC and that it is read, signed and dated by all subjects subsequently 
enrolled in the trial as well as those currently enrolled in the trial, as recommended by the 
the governing IRB. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This trial is to be conducted in accordance with Institutional Review Board regulations 
(U.S. 21 CFR Part 56.103). Only an IRB/IEC approved version of the informed consent 
form will be used. 
 
11.2 Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that originated with 
the Declaration of Helsinki. 
 
11.3 Subject Confidentiality 
All personal trial subject data collected and processed for the purposes of this trial 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 CRO, the sponsor, the IRB/IEC 
approving this trial, the FDA, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted direct 


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access to the trial subject’s original medical and trial records for verification of the data 
and/or clinical trial procedures. Access to this information will be permitted to the 
aforementioned individuals to the extent permitted by law. 
 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the IMP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s trial subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and EKGs. The investigator’s electronic copy of the eCRFs serves as the 
investigator’s record of a subject’s trial-related data. 
11.4.1 Retention of Documentation 
All trial related correspondence, subject records, consent forms, record of the distribution 
and use of all IMP and copies of case report forms should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region; or until at least 
two years have elapsed since the formal discontinuation of clinical development of the IMP. 
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. The investigator must notify the sponsor prior to destroying trial documentation 
even after the above-mentioned time has passed. 
 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping trial records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
 
11.5 Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs) 
All subject data will be captured in the subject source documents which will be entered  
into the eCRFs in the Electronic Data Capturing System (EDC). The investigator is 
responsible for ensuring that trial data is completely and accurately recorded in the source 
documents, data entered into each subject’s eCRF, and all trial-related materials. All trial 
data should also be attributable, legible, contemporaneous, and original. Recorded data 
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).  
 


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The EDC system is conforms to 21 CFR Part 11 requirements and data entry into the system 
will be performed only by staff that have been trained and have access to the system. An 
audit trail will be maintained within the system to capture all changes made within the 
database. After the end of the trial and database lock, copies of all applicable subjects’ 
eCRFs will be provided to each investigator site to be maintained on file by the investigator. 
 
11.6 Monitoring and Quality Assurance 
During the course of the trial a clinical research associate (CRA) will make routine site 
visits to review protocol compliance, assess IMP accountability, and ensure the trial 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 trial monitoring (including medical monitoring) will 
be outlined in a monitoring plan. 
Domestic and foreign regulatory authorities, and quality assurance, sponsor 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 with consideration to data 
protection as well as subject confidentiality to the extent that local, state, and federal laws 
apply. 
 
11.7 Handling of Biological Specimens 
Not applicable. 
 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved 
in the trial. Authorship will be established before writing the manuscript. The trial sponsor 
will have the final decision regarding authorship, manuscript and publication. 
 
 
 
 
 
 
 
 
 


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12 REFERENCES 
1. Benitez-del-Castillo J, Labetoulle M, Baudouin C, et al. (2017). Visual acuity and 
quality of life in DED: Proceedings of the OCEAN group meeting. The Ocular Surface 
15, 169-178. 
2. Craig, J. P. (2017). TFOS DEWS II Definition and Classofocation Report. The Ocular 
Surface, 15, 276-283. 
3. Le Q, Zhou X, Ge L, Wu L, Hong J, Xu J. Impact of dry eye syndrome on vision-related 
quality of life in a non-clinic-based general population. BMC Ophthalmology 2012; 
12(22): 1-8 
4. Lemp M. Report of the National Eye Institute/Industry Workshop on Clinical Trials in 
Dry Eyes. CLAO J. 1995; 21 (4): 221‐32. 
5. Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. Prevalence of dry eye among 
an elderly Chinese population in Taiwan: the Shihpai Eye Trial. Ophthalmology 2003; 
110(6):1096-101. 
6. McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The 
epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998; 105(6):1114-
9. 
7. Novack GD, Penny A, Barabino S, Bergamini MVW, Ciolino JB, Foulks GN, Goldstein 
M, Lemp MA, Schrader S, Woods C, Stapleton F. TFOS DEWS II Clinical Trial Design 
Report. The Ocular Surface 2017: 635-655. 
8. Pflugfelder SC, de Pavia CS. The pathophysiology of dry eye disease. What we know 
and future directions for research. Ophthalmology 2017; 124: S4-S13. 
9. Schaumberg DA, Sullivan DA, Dana MR. (2002). Epidemiology of dry eye syndrome. 
Adv Exp Med Biol, 506, 989-98. 
10. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. (2003). Prevalence of dry eye 
syndrome among US women. Am J Ophthalmol, 136, 318-26. 
11. Schaumberg DA, Dana R, Buring JE, Sullivan DA (2009). Prevalence of dry eye disease 
among US men: estimates from the Physician's Health Studies. Arch Ophthalmol, 127, 
763-8. 
12. Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W. Utility 
Assessment among patients with dry eye disease. Ophthalmology 2003; 110: 1412-
1419. 
13. Van Setten G, Labetoulle M, Baudouin C, Rolando M. Evidence of seasonality and 
effects of psychometry in dry eye disease. Acta Ophthalmol. 2016: 1-8. 
 
 






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5. Put the screw cap back on after administration. 
 
If a subject has difficulties with step 4 to 7 of Figure A, advise to refer to step 2 of  
Figure B: subject to squeeze bottle very gently or to wait until drop drips from the bottle 
without squeezing. 
 
 


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Appendix 4  Amendment Summary of Changes 
 
Page 
Original Text 
Amended Text (in bold) 
Rationale 
1 
Version 1.0 
Version 2.0 
New version of 
protocol 
1 
 
Amendment 1: 09 NOV 2020 
Generation of 
Amendment 1 
2 
 
 
Correction 
5, 27 
6. Have 
abnormal 
lid 
anatomy 
that 
causes 
incomplete eyelid closure 
including entropion and 
ectropion or floppy lid 
syndrome that exposes 
parts of the conjunctiva or 
impairs 
the 
blinking 
function of the eye.    
6. Have abnormal lid anatomy that 
causes incomplete eyelid closure 
including entropion and ectropion 
or floppy lid syndrome that 
exposes parts of the conjunctiva 
or impairs the blinking function of 
the eye (e.g. Botox injections for 
blepharospasm). 
Added 
clarification 
7, 28 
 
31. Have a history of isotretinoin 
(e.g. 
Accutane, 
Myorisan, 
Claravis, Amnesteem) use. 
Added 
36 
 
• History of isotretinoin use  
Added 
43 
The expectedness of an AE 
should be determined based 
upon existing safety 
information about the IMP. 
The expectedness of a treatment 
emergent AE should be determined 
based upon existing safety 
information about the IMP. 
Clarification 
43 
• Not Applicable: Any AE 
that is unrelated to the 
IMP. 
• Not Applicable: Any AE with an 
onset prior to first dose of IMP. 
 
Clarification 
73 
 
Appendix 4: Summary of Changes 
Added 
74 
 
Amendment 1 Date: 09 NOV 2020 
Generation of 
Amendment 1 
75 
 
Amendment 1 Date: 09 NOV 2020 
Generation of 
Amendment 1 
 
 




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Appendix 6  Investigator’s Signature 
Protocol Title: 
A Phase 3, Multi-Center, Randomized, Double-Masked, 
Saline-Controlled Trial to Evaluate the Effect of NOV03 
(Perfluorohexyloctane) on Signs and Symptoms of Dry Eye 
Disease Associated with Meibomian Gland Dysfunction 
(Mojave Study) 
Protocol Number: 
904 
Date: 
05 AUG 2020  
Amendment 1 Date: 
09 NOV 2020 
 
 
I agree to implement and conduct the trial 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 CRO and the sponsor in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Ethical Review Committee (ERC) or 
another group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number: