Clinical trial NCT03333057
Conditions: Dry Eye Disease (DED)
Sponsor: Novaliq GmbH
Start date: 2018-01-03; Completion date: 2018-07-27
Enrollment: 336 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety and tolerability of perfluorohexyloctane (NOV03) at two different dosing regimens compared to saline solution in subjects with Dry Eye Disease (DED).

Detailed description:

Arms: arm 1: Perfluorohexyloctance solution 4 times daily (QID) arm 2: Perfluorohexyloctance solution 2 times daily (BID) arm 3: Saline solution (0.9% sodium chloride solution) 4 times daily (QID) arm 4: Saline solution (0.9% sodium chloride solution) 2 times daily (BID)
Interventions: intervention 1: NOV03 intervention 2: Placebo
Intervention descriptions: intervention 1: Perfluorohexyloctane intervention 2: Saline solution (0.9% sodium chloride solution)

Protocol documents:
Prot_SAP_000.pdf: 
NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
 
Confidential 
Page 1 of 88 
 
Clinical Trial Protocol 
Protocol Title: 
A Phase 2, Multi-Center, Randomized, Double-Masked, 
Saline-Controlled Study to Evaluate the Effect of 
Perfluorohexyloctane (NOV03) at Two Different Dosing 
Regimens on Signs and Symptoms of Dry Eye Disease. 
Protocol Number: 
NVU-002 
Study Phase: 
2 
Product Name: 
NOV03 (
 Perfluorohexyloctane) 
IND Number: 
130588 
Indication: 
Dry Eye Disease (DED) 
Sponsor: 
NOVALIQ GmbH 
Im Neuenheimer Feld 515 
69120 Heidelberg 
Germany 
Contract Clinical 
Research Organization 
 
 
 
Version: 
2.0 
Amendment 1: 
07 December 2017 
 
             
Original Protocol Date: 
13 October 2017 
 
 
________________________________________________________________________ 
Confidentiality Statement 
This protocol contains confidential, proprietary information of NOVALIQ, GmbH. Further 
dissemination, distribution or copying of this protocol or its contents is strictly prohibited. 
Regulatory Statement 
This study will be performed in compliance with the protocol and in accordance with 
Good Clinical Practice (International Conference on Harmonisation [ICH], Guidance E6, 
1996), principles of human subject protection, and applicable country-specific regulatory 
requirements. 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
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STUDY CONTACT INFORMATION 
NOVALIQ GmbH 
Role in the Study  
Name and Contact Information 
Manager Clinical 
Development: 
 
 
 
 
 
 
VP Preclinical & Clinical 
Development: 
 
 
 
 
 
 
MEDICAL MONITOR 
Medical Monitor:  
 
  
 
    
 
  
 
PRODUCT SAFETY 
Sr. Product Safety Associate:  
 
 
  
 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
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SYNOPSIS 
Protocol Title: 
A Phase 2, Multi-Center, Randomized, Double-
Masked, Saline-Controlled Study to Evaluate the 
Effect of Perfluorohexyloctane (NOV03) at Two 
Different Dosing Regimens on Signs and Symptoms 
of Dry Eye Disease 
Protocol Number: 
NVU-002 
 
Study Drug: 
NOV03 (
 Perfluorohexyloctane) 
Control: 
Saline solution: 0.9% sodium chloride solution  
Study Phase: 
2 
Study Objective: 
The primary objective for this study is to evaluate 
the efficacy, safety, and tolerability of 
perfluorohexyloctane (NOV03) at two different 
dosing regimens compared to saline solution in 
subjects with Dry Eye Disease. 
 
 
 
 
 
 
 
Overall Study Design 
 
Structure: 
Multi-center, randomized, double-masked, saline-
controlled 
Duration: 
An individual subject’s participation is estimated to 
be approximately 10 weeks. 
Dosage/Dose Regimen: 
Subjects eligible to be randomized will receive one 
of the following treatments to be administered 
bilaterally from Visit 1 to Visit 4. 
1) NOV03 (
 Perfluorohexyloctane)  
4 times daily (QID)  
2) NOV03 (
 Perfluorohexyloctane) 
2 times daily (BID) 
3) Saline solution (0.9% sodium chloride solution) 
QID 
4) Saline Solution (0.9% sodium chloride solution), 
BID 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
 
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Summary of Visit Schedule: 
5 visits over the course of approximately 10 weeks 
• Visit 0 = Within 14 days before Visit 1, 
Screening 
• Visit 1 = Day 1, Baseline/Randomization 
• Visit 2 = Day 15 ± 1 days, 2-week follow-up 
• Visit 3 = Day 29 ± 2 days, 4-week follow-up 
• Visit 4 = Day 57 ± 2 days, 8-week follow up 
/Study Exit 
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, double-
masked, multi-center study.  
 
Study Population Characteristics 
Number of Subjects: 
Approximately 
 subjects will be screened to 
enroll at least 300 subjects (100 each for the two 
active arms, and 50 each for the two saline solution 
arms) subjects at up to 15 sites. 
Condition/Disease: 
Dry Eye Disease (DED)  
Inclusion Criteria:  
Subjects must: 
a. Be at least 18 years of age. 
b. Provide written informed consent. 
c. Have a subject reported history of Dry Eye 
Disease 
 
. 
d. Have Tear film break-up time (TFBUT) 
 
at Visit 0 and Visit 1. 
e. Have Ocular Surface Disease Index (OSDI) 
 at Visit 0 and Visit 1. 
f. Have a Schirmer’s Test I 
 mm at Visit 0 and 
Visit 1. 
g. Have Meibomian Gland Dysfunction (MGD) 
defined as MGD score 
 
 
 
 
 
 
 
 
 
 
 
at Visit 0 and Visit 1. 
 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
 
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h. Have a total corneal fluorescein staining score 
of  
 
 
 
 
 
   
i. Have at least one eye (the same eye) satisfy all 
criteria for d, f, g, and h above at Visit 0 and 
Visit 1. 
j. Be able and willing to follow instructions, 
including participation in all study assessments 
and visits. 
Exclusion Criteria:  
Subjects must not: 
a. Have any clinically significant slit-lamp 
findings at Visit 0 and/or in the opinion of the 
investigator have any findings that may interfere 
with study parameters, and may include eye 
trauma or history of eye trauma. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
e. Have abnormal lid anatomy (incomplete eyelid 
closure, entropion, ectropion) that exposes parts 
of the conjunctiva or impairs the blinking 
function of the eye. 
 
 
 
 
 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
 
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h. Have an ocular or periocular malignancy. 
 
 
  
j. Have a history of herpetic keratitis. 
k. Have active ocular allergies or ocular allergies 
that are expected to be active during the study 
period. 
l. Be diagnosed with an ongoing ocular or 
systemic infection (bacterial, viral, or fungal), 
including fever and current treatment with 
antibiotics. 
m. Have worn contact lenses within 1 month of 
Visit 0 or anticipate using contact lenses during 
the study. 
 
 
 
 
 
 
 
 
 
 
p. Be a woman who is pregnant, nursing or 
planning a pregnancy. 
q. Be unwilling to submit to a blood pregnancy test 
at Visit 0 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 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
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bilateral oophorectomy), or is post-menopausal 
(without menses for 12 consecutive months). 
r. 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 study, she must agree to use adequate 
birth control as defined above for the remainder 
of the study. 
s. Have an uncontrolled systemic disease. 
t. Have a known allergy and/or sensitivity to the 
study drug or saline components.  
 
 
 
 
 
 
 
 
 
w. Have used any topical steroids treatments, 
topical cyclosporine, lifitegrast, serum tears or 
topical anti-glaucoma medication within 60 
days prior to Visit 0. 
 
 
 
 
 
 
 
 
 
 
y. Have corrected visual acuity greater than or 
equal to logarithm of the minimum angle of 
resolution (logMAR), 
 as assessed by Early 
Treatment of Diabetic Retinopathy Study 


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Clinical Trial Protocol # NVU-002 
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(ETDRS) scale in both eyes at Visit 0 and Visit 
1. 
 
z. 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 study results, or may interfere 
significantly with the subject’s participation in 
the study. 
 
Study Formulations: 
• 
 Perfluorohexyloctane  
 
• Saline Solution (0.9% sodium chloride 
solution) 
 
Evaluation Criteria 
 
Efficacy Endpoint(s):  
Primary Efficacy Endpoints: 
The following primary endpoints will be tested: 
• Corneal Fluorescein Staining (CFS) total 
(NEI grading) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
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Safety Endpoints: 
•
Visual Acuity.
•
Slit-Lamp Biomicroscopy.
•
Intraocular Pressure.
•
Dilated Fundoscopy.
•
Hematology/Chemistry parameters.
•
Systemic and ocular adverse events.
•
Symptoms directly related to the instillation
or use of the investigational medication
based on questionnaire/visual analogue
scale.
Other: 
•
Pharmacokinetics of perfluorohexyloctane
(blood levels for perfluorohexyloctane at
predefined time points and PK parameters as
appropriate).
General Statistical Methods and Types of Analyses 
Sample Size 
At least 300 subjects (100 each for the two active arms, and 50 each for the two saline 
solution arms) will be randomly assigned to study treatment such that approximately 
90 evaluable participants per active arm and 45 per saline solution arm complete the 
study, assuming a 10% dropout rate. 
Primary Efficacy Analyses: 
The primary evaluation of efficacy of the active arms will be against a combined 
control arm (with BID and QID saline solution). Sensitivity analysis may be 
undertaken for dosing-regimen matching control (that is, QID active vs. QID saline 
solution). 
The primary analysis will be performed to compare the week 8 difference in the 
change from baseline in CFS between the active NOV03 groups and the saline 
solution groups. The comparison will be conducted using a repeated measures model 
with treatment, site, visit, and treatment by visit interaction fixed categorical factors, 
baseline as a continuous covariate, and using an unstructured covariance matrix. To 
establish evidence of efficacy in this proof of concept study, the hypothesis tests will 
be one-sided and performed at the 0.05 significance level. 
 
 
 
 


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 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
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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 
group. An AE is treatment emergent if it occurs or worsens after the patient signed 
Informed Consent Form (ICF). 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 AEs. 
Pharmacokinetics 
Whole blood for perfluorohexyloctane blood concentration measurements will be 
drawn from a minimum of 66 subjects at least at one investigational site with the goal 
of having samples from 20 subjects per treatment arm. Blood concentrations of 
perfluorohexyloctane will be summarized descriptively. If possible, the following PK 
parameters will be estimated: AUC0-, Cmax, tmax and summarized descriptively.  


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................3 
TABLE OF CONTENTS ................................................................................................11 
LIST OF ABBREVIATIONS .........................................................................................15 
1 
INTRODUCTION...................................................................................................17 
1.1 
Dry Eye Disease (DED) .........................................................................................17 
1.2 
Product Rationale ..................................................................................................17 
1.3 
Trial Rationale .......................................................................................................17 
1.4 
Summary of Known and Potential Risks and Benefits to Human Subjects ....18 
2 
STUDY DESIGN .....................................................................................................19 
2.1 
Study Objectives ....................................................................................................19 
2.1.1 
Primary Objective .............................................................................19 
 
 
2.1.3 
Primary Endpoints ............................................................................19 
 
 
2.2 
Overall Study Design and Investigational Plan ..................................................20 
2.3 
End of Study Definition ........................................................................................20 
2.4 
Visit Description ....................................................................................................20 
2.5 
Study Flow ..............................................................................................................21 
2.6 
Enrollment and Treatment Assignment ..............................................................22 
3 
STUDY POPULATION .........................................................................................24 
3.1 
Number of Subjects (approximate) ......................................................................24 
3.2 
Study population characteristics ..........................................................................24 
3.3 
Inclusion Criteria ..................................................................................................24 
3.4 
Exclusion Criteria ..................................................................................................25 
3.5 
Re-Screen Procedures ...........................................................................................27 
3.6 
Subject Withdrawal Criteria ................................................................................27 
4 
STUDY PARAMETERS ........................................................................................28 
4.1 
Efficacy Measures ..................................................................................................28 
4.1.1 
Primary Efficacy Variables ...............................................................28 
 
 
4.2 
Safety Measures .....................................................................................................28 
4.3 
Other .......................................................................................................................28 
5 
STUDY MATERIALS ............................................................................................29 
5.1 
Study Drug(s) .........................................................................................................29 
5.1.1 
Formulations .....................................................................................29 
5.2 
Study Drug Storage ...............................................................................................30 
5.3 
Study Drug Preparation .......................................................................................30 
5.4 
Administration of Study Drug ..............................................................................30 
5.4.1 
Dispensation Schedule ......................................................................31 
5.5 
Study Drug Accountability ...................................................................................31 
5.6 
Study Drug Handling and Disposal .....................................................................32 
6 
STUDY METHODS AND PROCEDURES .........................................................33 
6.1 
Concurrent Therapies ...........................................................................................33 
6.2 
Prohibited Medications .........................................................................................33 
6.3 
Restrictions and Prohibitions ...............................................................................33 


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 Perfluorohexyloctane) 
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Clinical Trial Protocol # NVU-002 
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6.4 
Examination Procedures .......................................................................................33 
6.4.1 
Procedures to be performed at each study visit with regard to study 
objective(s) .....................................................................................................33 
6.4.2 
Early Termination/Discontinuation ..................................................39 
6.4.3 
Unscheduled Visits ...........................................................................40 
6.4.4 
Pharmacokinetic Samples .................................................................40 
6.5 
Compliance with Protocol .....................................................................................41 
6.6 
Subject Disposition ................................................................................................41 
6.6.1 
Completed Subjects ..........................................................................41 
6.6.2 
Discontinued subjects .......................................................................41 
6.7 
Study Termination ................................................................................................41 
6.8 
Study Duration ......................................................................................................42 
6.9 
Monitoring and Quality Assurance .....................................................................42 
7 
ADVERSE EVENTS ..............................................................................................43 
7.1 
Adverse Event ........................................................................................................43 
7.1.1 
Severity .............................................................................................43 
7.1.2 
Relationship to Study Drug ...............................................................43 
7.1.3 
Expectedness .....................................................................................44 
7.2 
Serious Adverse Events .........................................................................................44 
7.3 
Procedures for Reporting Serious Adverse Events ............................................45 
7.3.1 
Reporting a Serious Adverse Event ..................................................45 
7.3.2 
Reporting a Suspected Unexpected Serious Adverse Reaction 
(SUSAR) ........................................................................................................46 
7.4 
Procedures for Unmasking of Study Drug ..........................................................47 
7.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ...........47 
8 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES................48 
8.1 
Analysis Populations .............................................................................................48 
8.2 
Statistical Hypotheses ............................................................................................48 
8.3 
Sample Size ............................................................................................................49 
8.4 
Statistical Analysis .................................................................................................49 
8.4.1 
General Considerations .....................................................................49 
8.4.2 
Unit of Analysis ................................................................................49 
8.4.3 
Missing Data .....................................................................................50 
8.4.4 
Multiplicity Consideration ................................................................50 
8.4.5 
Primary Efficacy Analyses ...............................................................50 
 
 
8.4.7 
Safety Variables ................................................................................51 
8.4.8 
Pharmacokinetic Variables ...............................................................52 
9 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................53 
9.1 
Protection of Human Subjects..............................................................................53 
9.1.1 
Subject Informed Consent.................................................................53 
9.1.2 
Institutional Review Board (IRB) Approval .....................................53 
9.2 
Ethical Conduct of the Study ...............................................................................53 
9.3 
Subject Confidentiality .........................................................................................53 
9.4 
Documentation .......................................................................................................54 


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 Perfluorohexyloctane) 
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Clinical Trial Protocol # NVU-002 
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9.4.1 
Retention of Documentation .............................................................54 
9.5 
Labeling, Packaging, Accountability, and Return or Disposal of Study Drug 54 
9.5.1 
Labeling/Packaging...........................................................................54 
9.5.2 
Accountability of Study Drug ...........................................................55 
9.5.3 
Return or Disposal of Study Drug ....................................................55 
9.6 
Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ...................................................................................................................55 
9.7 
Publications ............................................................................................................55 
9.8 
Handling of Biological Specimens ........................................................................56 
10 
SELECTED REFERENCES .................................................................................58 
11 
APPENDICES .........................................................................................................59 
 
LIST of APPENDICES 
 
Appendix 1 
Schedule of Visits and Measurements (in recommended order) ..... 60 
Appendix 2 
Instructions for Administration of Eye Drops .................................. 62 
Appendix 3: 
Examination Procedures, Tests, Equipment, and Techniques ........ 63 
Appendix 4: 
Blood Samples for PK: Handling, Storage, and Shipping ............... 81 
Appendix 5: 
Amendment Summary of Changes..................................................... 82 
Appendix 6: 
Sponsor and 
 Approvals .......................................................... 87 
Appendix 7: 
Investigator’s Signature ...................................................................... 88 
 


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 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
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LIST OF TABLES 
 
Table 1. 
NVU-002 Study Flow Chart ........................................................................ 22 
Table 2. 
Active Investigational Product .................................................................... 29 
Table 3. 
Control/Reference Investigational Product ............................................... 30 
Table 4. 
Blood Volumes for Safety Laboratory Tests and Pharmacokinetics ....... 56 
Table 5.   Clinical Laboratory Tests ............................................................................ 57 
 
 
LIST OF FIGURES 
Figure 1. Proper Handling of Eye drop Container ....................................................... 62 
 
 
 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AUC0-last 
Area under the blood concentration time curve from time 
0 to time of last measureable concentration  
BAC 
benzalkonium chloride 
BCVA 
best-corrected visual acuity 
BID 
Two times daily 
CFR 
Code of Federal Regulations 
Cmax 
Maximum blood concentration 
CRF 
case report form 
CV 
Coefficient of variation 
DED 
Dry Eye Disease 
DEWS 
Dry Eye Workshop 
eCRF 
electronic case report form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
investigational new drug  
IOP 
intraocular pressure 
IRB 
institutional/independent review board 
IUD 
Intra-uterine device 
IWRS 
interactive web response system 
logMAR 
logarithm of the minimum angle of resolution 
LLT 
lipid layer thickness 
LS mean 
Least square mean 
MCH 
Mean cell hemoglobin 
MCHC 
Mean cell hemoglobin concentration 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
meibomian gland dysfunction 
mITT 
modified intent-to-treat 
NEI 
National Eye Institute 
NOV3 
 perfluorohexyloctane 
OD 
right eye 
OS 
left eye 
OSDI© 
ocular surface disease index 
PP 
per protocol 
QID 
four times a day 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 


NOV03 (
 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
07 December 2017 FINAL V2.0 
 
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TEAEs 
Treatment-emergent adverse events 
TFBUT 
tear film break-up time 
TFT 
tear film thickness 
tmax 
time to Cmax 
VA 
visual acuity 
VAS 
visual analog scale 
 
 


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Clinical Trial Protocol # NVU-002 
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1 INTRODUCTION 
1.1 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.2 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 2030.4,5,6 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.1  
1.2 Product Rationale 
NOV03 is a sterile ophthalmic eye drop formulation, developed for the treatment of the 
signs and symptoms of DED associated with meibomian gland dysfunction (MGD). 
It is a one component product consisting of 
 perfluorohexyloctane developed to 
supplement the lipid layer leading to reduced evaporation of the tear film and thereby 
protecting the ocular surface. As a single component product, it is free of excipients like 
oils, surfactants and preservatives. NOV03 is developed with the goal to provide patients 
with DED due to MGD an effective treatment option with a new mode of action addressing 
directly the lipid layer. Further advantages compared to existing therapies including 
convenient handling, improved tolerability, and a decrease in the visual disturbance 
associated with oily eye drops, emulsions or ointments. 
The 
sole 
ingredient 
of 
NOV03 
is 
the 
anhydrous 
semifluorinated 
alkane, 
perfluorohexyloctane 
 
. Liquid 
semifluorinated alkanes are physically, physiologically and chemically inert, colorless, 
laser stable compounds with the same refractory index as water. They do not undergo 
metabolism in the human body.3 Perfluorohexyloctane shows a low surface tension of 19.65 
mNm, which leads to excellent spreading activities on the ocular surface and to the 
formation of small droplet. On the ocular surface, NOV03 forms a thin film together with 
tear lipids thereby supporting the lipid layer, which in its natural function to reduce the 
evaporation of the tear film and reducing sharing forces. 
1.3 Trial Rationale 
NOV03 might be valuable for patients with DED due to MGD, as the loss of the lipid layer 
in these patients leads to increased evaporation of the tears. Initial clinical data from 
observational studies NT-0017 and NT-0028 consistently indicate that NOV03 is efficacious 
in treating signs and symptoms of mild to moderate evaporative DED and mild to moderate 


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 Perfluorohexyloctane) 
Sponsor: NOVALIQ GmbH 
Clinical Trial Protocol # NVU-002 
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DED and MGD. A mechanistic clinical study NT-004 demonstrated that NOV03 increase 
tear film thickness (TFT) and lipid layer thickness (LLT) over saline solution, and therefore 
provides further clinical evidence supportive for this indication. 
This first US study is designed to investigate the efficacy and safety in a larger population 
versus a control in a double masked fashion. It is powered to demonstrate efficacy for a 
sign endpoint total CSF (NEI grading). Other sign and symptom endpoints will be explored 
as well as the dosing regimen. 
Data from this study will serve to plan the phase 3 program for the project.  
1.4 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. Perfluorohexyloctane has been 
on the market as a medical device in the European Union for more than 10 years in 
ophthalmology, approved as a temporary endotamponade and an intraoperative instrument 
for retinal surgery. It is not yet approved in the US. Physical properties such as low surface 
and interface tension, colorlessness and notably complete physical and chemical inertness 
make this substance class suitable for the topical ophthalmic application. 
A total of 151 subjects have been treated with NovaTears® (NOVALIQ GmbH, Heidelberg, 
Germany) in four post-marketing studies, with a treatment duration between 4 and 12 
weeks. 
Safety and local tolerability of NovaTears® during these four post marketing studies was 
found to be excellent when used at the recommended dose of one drop per eye, 4 times a 
day. In all four studies, no changes in intraocular pressure (IOP) or best-corrected visual 
acuity (BCVA) was observed, nor were clinically significant findings with slit lamp 
examinations. Out of a total of 151 patients across four post market studies, 27 AEs were 
reported from 17 subjects treated with NovaTears®, 12 of which were considered possibly, 
probably or definitely related to the use of NovaTears®. All cases reported to be related 
described symptoms of mild to moderate ocular irritation, which disappeared shortly after 
discontinuation of the product. No serious adverse events (SAEs), incidents or deaths 
occurred. 
Furthermore, market vigilance data collected to date from >1 million bottles dispatched in 
the market confirms the good safety profile, with only 64 medical complains as of 30 June 
2017. The vast majority of these medical complaints were mild cases of ocular irritations. 
The observational studies consistently indicate that NOV03 is efficacious in treating signs 
and symptoms of mild to moderate evaporative DED and mild to moderate DED caused by 
MGD. A statistically significant increase in tear film fluid was observed in study NT-001, 
while tear film stability, as assessed by TFBUT, was shown to significantly improve in both 
the NT-001 and NT-002 studies. Comparable to these results, a significant decrease in the 
average OSDI© score was also observed in studies NT-001 and NT-002 together with 
decreases in the intensity of corneal staining (and conjunctival staining in NT-002). No 


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change was observed for any of these parameters in NT-003 in patients with DED due to 
GvHD. Study NT-004 demonstrated that NovaTears® increase TFT and LLT over saline 
solution, and therefore provides further clinical evidence supportive of the mode of action 
of NovaTears®.  
In summary, based on the preclinical and clinical data obtained to date, risks to subjects in 
the planned NVU-002 study are considered very low. Furthermore, the subjects randomized 
in the study will be closely monitored, and current standard ophthalmological safety 
assessments will be performed during the entire treatment period in the study at 2, 4 and 8 
weeks. The efficacy demonstrated to date is supportive of increased benefits in addressing 
the evaporative aspects of DED by strengthening the lipid layer, and suggests relief of DED 
symptoms and signs, that is possibly more sustainable than comparator saline treatments. 
NOV03 therefore provides a favorable risk-benefit treatment profile to patients with mild 
to moderate DED and the NVU-002 study is designed to further assess this positive profile. 
2 STUDY DESIGN 
2.1 Study Objectives 
2.1.1 Primary Objective 
• The primary objective for this study is to evaluate the efficacy, safety, and 
tolerability of perfluorohexyloctane (NOV03) at two different dosing regimens 
compared to saline solution in subjects with Dry Eye Disease 
 
 
 
 
 
 
 
 
2.1.3 Primary Endpoints 
• Total CFS (NEI Grading Scale) at Day 57.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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2.2 Overall Study Design and Investigational Plan 
This study is a phase 2, multi-center, randomized, double-masked, saline-controlled study 
to evaluate the effect of NOV03 (
perfluorohexyloctane) at two different dosing 
regimens on signs and symptoms of Dry Eye Disease. Approximately 300 male and female 
subjects of at least 18 years of age with a subject-reported history of DED in both eyes and 
who meet all other study eligibility criteria will be randomized, stratified by site, 2:2:1:1 to 
receive 1 of 4 treatments: 
Treatment 1: NOV03 (
 Perfluorohexyloctane), 4 times daily (QID) 
Treatment 2: NOV03 (
Perfluorohexyloctane), 2 times daily (BID) 
Treatment 3: Saline (0.9% sodium chloride solution), QID 
Treatment 4: Saline (0.9% sodium chloride solution), BID 
Each active treatment group will be comprised of 100 subjects and each saline group will 
be comprised of 50 subjects such that approximately 90 evaluable subjects per active arm 
and 45 per saline arm complete the study. Up to 15 sites are anticipated to participate. 
This study will consist of two periods: a 14-day screening period and a 57-day treatment 
period (See Appendix 1).  
2.3 End of Study Definition  
The end of the study for an individual patient is defined as that patient’s last clinic visit.  
The end of the study for the overall trial is defined as the finalization of the Clinical Study 
Report. 
2.4 Visit Description  
Refer to Appendix 1 for the Schedule of Visits and Measurements and Table 1 for the 
Study Flow Chart. 
Screening (Visit 0) 
Subjects will be required to sign an Informed Consent before completing any study related 
procedure. At the screening visit, vital signs will be assessed and the subject will give blood 
for safety laboratory tests. They will also submit to a battery of tests to confirm the extent 
and severity of their symptoms and objective signs of dry eye. At least one eye must qualify 
with the following objective measures: Tear film break up time 
, Schirmer’s Test 
 
, and Meibomian gland dysfunction (MGD) defined as MGD score 
. 


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Subjects who fail to qualify for the study at screening may be rescreened as described in 
section 3.5 
Baseline Visit Day 1 (Visit 1) 
On Day 1 (Visit 1), eligible subjects will be evaluated for baseline signs and symptoms of 
dry eye disease. After randomization subjects at selected sites will give a blood sample to 
be used for PK. Subjects will be given a 14-day supply and will self-administer a single 
drop of the study medication into each eye at the clinic. Each subject will be given a diary 
to record that their doses were taken. Study staff will help the subject to understand how to 
use the diary and when the remaining doses should be taken. 
Visits 2-4 
Subjects will return to the clinic on Day 15±1 (Visit 2), 29±2 (Visit 3), and 57±2 (Visit 4) 
to be evaluated for signs and symptoms of dry eye disease. During this period, subjects will 
dose NOV03 or the saline solution QID and BID, depending on their assigned group. The 
unused portion of the study medication should be returned to the clinic and a new study 
medication kit will be dispensed. The diary will be checked. At Visit 4, vital signs will be 
evaluated and a second blood draw will be performed for PK at selected sites. The diary 
will be collected at the clinic during each visit. Subjects will be dismissed from the study 
after all Visit 4 assessments have been completed. 
Early Termination 
Subjects who terminate early during the treatment period will be asked to complete all 
safety assessments as indicated on Visit 4 on the Schedule of Visits and Measurements prior 
to commencement of any alternative dry eye therapy (if at all possible). Subjects who are 
terminated early from the study will not be replaced. 
2.5 Study Flow  
All subjects will be expected to progress from screening through study exit. 
 
 
There are no other side studies and all subjects will be 
evaluated according to Table 1: 


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Table 1. 
NVU-002 Study Flow Chart 
Visit 0 
(Within 14 days before Visit 
1): 
Screening 
Informed Consent (incl. HIPAA) 
Demographics, Medical/Medication & Ocular 
History, AE Query 
Symptom Questionnaires, Visual Acuity 
Eye Evaluations 
IOP / Dilated Fundoscopy 
Blood pressure and heart rate 
Blood Draw for Safety Labs (including pregnancy 
tests) 
Visit 1 
(Day 1): 
Baseline/Randomization 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Eye Evaluations 
Randomization 
PK Predose Blood Draw (specific sites only) 
Study Drug Dispensed 
PK Postdose Blood Draws (specific sites only) 
Visit 2 
(Day 15 ± 1): 
2-week follow-up 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Eye Evaluations 
Study Drug Dispensed 
Visit 3 
(Day 29 ± 2): 
4-week follow-up 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Eye Evaluations, IOP 
Study Drug Dispensed 
Visit 4 
(Day 57 ± 2) 
8 –week follow up / Study 
Exit 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Blood pressure and heart rate 
Symptom Questionnaires, Visual Acuity 
Eye Evaluations 
IOP / Dilated Fundoscopy 
Blood Draw for Safety Labs (including pregnancy 
tests) 
PK Blood Draw at the end of the visit (specific sites 
only) 
HIPAA = Health Information Portability and Accountability Act 
IOP = intraocular pressure 
AE = adverse event 
PK = pharmacokinetic 
2.6 Enrollment and Treatment Assignment  
All dose groups will be enrolled in parallel. Each subject will be assigned a unique 
screening number. All screening numbers will be assigned in strict numerical sequence at 
a site and no numbers will be skipped or omitted. If all inclusion and exclusion criteria are 
met at Visits 0 and 1, each qualifying subject will then be assigned a randomization number. 
Once a randomization number has been assigned it must not be reassigned. 
 
 The Interactive Web Response System (IWRS) will be 
used to account for the stratification factor while assigning the randomization number. The 
subjects, investigators and sponsor will be masked to study treatment assignment. 


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Each subject will spend approximately 10 weeks in the study. The total duration of the study 
from first patient in to last patient out is expected to be 24 weeks (6 months).   
 
 


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3 STUDY POPULATION 
3.1 Number of Subjects (approximate) 
It is estimated that approximately 
 subjects will be screened. At least 300 participants 
will be randomly assigned to study treatment such that approximately 90 evaluable 
subjects per active arm and 45 per saline arm complete the study. 
3.2 Study population characteristics 
All subjects must be at least 18 years of age, and may be of either gender, and of any race. 
Subject must meet all inclusion criteria and none of the exclusion criteria. 
3.3 Inclusion Criteria 
Subjects will be eligible to participate in this study if they meet all of the following criteria  
a. 
Male or female subjects, of age ≥18 years (inclusive) at the time of signing 
the informed consent form (ICF). 
b. 
Provide written informed consent. 
c. 
Have a subject reported history of Dry Eye Disease 
 
 
d. 
Have Tear Film Break Up Time 
 sec. at Visit 0 and Visit 1. 
e. 
Have Ocular Surface Disease Index (OSDI©) 
 at Visit 0 and Visit 1. 
f. 
Have a Schirmer’s Test I 
 mm at Visit 0 and Visit 1. 
g. 
Have Meibomian Gland Dysfunction defined as MGD score 
 
 
  
at Visits 0 and 1. 
h. 
Have a total corneal fluorescein staining score of 
 
 
 
 
  
i. 
Have at least one eye (the same eye) satisfy all criteria for d, f, g, and h above 
at Visit 0 and Visit 1. 
 
j. 
Be able and willing to follow instructions, including participation in all study 
assessments and visits. 
 
 


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3.4 Exclusion Criteria 
Subjects will not be eligible to participate in this study if any of the following criteria 
apply: 
a. 
Have any clinically significant slit-lamp findings at Visit 0 and/or in the 
opinion of the investigator have any findings that may interfere with study 
parameters and may include eye trauma or history of eye trauma. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
e. 
Have abnormal lid anatomy (incomplete eyelid closure, entropion, 
ectropion) that exposes parts of the conjunctiva or impairs the blinking 
function of the eye. 
 
 
 
 
  
 
 
 
 
h. 
Have an ocular or periocular malignancy. 
 
 
 
j. 
Have a history of herpetic keratitis. 
k. 
Have active ocular allergies or ocular allergies that are expected to be active 
during the study period. 
l. 
Be diagnosed with an ongoing ocular or systemic infection (bacterial, viral, 
or fungal), including fever and current treatment with antibiotics. 
m. 
Have worn contact lenses within 1 month of Visit 0 or anticipate using 
contact lenses during the study. 


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p. 
Be a woman who is pregnant, nursing or planning a pregnancy. 
q. 
Be unwilling to submit to a blood pregnancy test at Visit 0 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). 
r. 
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; 
intra-uterine 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 
study, she must agree to use adequate birth control as defined above for the 
remainder of the study. 
s. 
Have an uncontrolled systemic disease. 
t. 
Have a known allergy and/or sensitivity to the study drug or saline 
components.  
 
 
 
 
 
 
 
w. 
Have used any topical steroids treatments, topical cyclosporine, lifitegrast, 
serum tears or topical anti-glaucoma medication within 60 days prior to Visit 
0. 
 
 
 
 
y. 
Have corrected visual acuity greater than or equal to logarithm of the 
minimum angle of resolution (logMAR) 
as assessed by the Early 


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Treatment of Diabetic Retinopathy Study (ETDRS) scale in both eyes at 
Visit 0 and Visit 1. 
z. 
Have a condition or be in a situation (including language barrier) that the 
investigator feels may put the subject at significant risk, may confound the 
study results, or may interfere significantly with the subject's participation 
in the study. 
3.5 Re-Screen Procedures  
If the patient does not qualify at Visit 0 or Visit 1, he or she may be re-screened after 14 
days from the relevant visit provided that new informed consent to be signed, new 
screening number received via IWRS and all the assessments are repeated as per 
protocol requirements. 
3.6 Subject Withdrawal Criteria  
Subjects may discontinue their participation in the study at any time without prejudice to 
further treatment. 
A subject may be discontinued after randomization from the study for any of the 
following reasons:  
• Noncompliance with the protocol as judged by the Investigator and/or the 
Sponsor;  
• Incorrect enrollment of the subject (requires discussion with the Sponsor); 
• If at any time during the study 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 AEs that present an unacceptable consequence or risk to the 
subject in the judgment of the Investigator, Sponsor, or the Medical Monitor;  
• Occurrence of pregnancy; 
• Withdrawal of consent. 
 
 
 
 


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4  STUDY PARAMETERS 
4.1 Efficacy Measures 
4.1.1 Primary Efficacy Variables 
The following primary endpoints will be tested: 
• Corneal Fluorescein Staining (CFS) total (NEI Grading Scale) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
4.2 Safety Measures 
• Visual Acuity 
• Slit-Lamp Biomicroscopy 
• Intraocular Pressure 
• Dilated Fundoscopy 
• Hematology/Chemistry parameters 
• Systemic and ocular AEs 
• Symptoms directly related to the instillation or use of the investigational 
medication based on questionnaire/visual analogue scale 
4.3 Other 
• Blood levels of perfluorohexyloctane at predefined time points. 


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5 STUDY MATERIALS 
5.1 Study Drug(s) 
5.1.1 Formulations 
NOV03 drug product is a thin clear, preservative-free ophthalmic drop (see Table 2). 
Saline eye drops, preserved with benzalkonium chloride will be supplied as the reference 
product (see Table 3). Study drug and control will be provided in identical bottles and 
labeling to ensure the double masked character of the trial. 
Table 2. 
Active Investigational Product 
 
Investigational Product 
Product code: 
NOV03 
Chemical name: 
Perfluorohexyloctane  
Molecular formula: 
 
Dosage form: 
3 mL ophthalmic solution 
Unit dose 
 
 perfluorohexyloctane 
Route of administration 
Topical ocular administration 
Physical description 
Colorless and clear ophthalmic solution 
Excipients: 
None 
Manufacturer: 
 
 
 


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Table 3. 
Control/Reference Investigational Product 
 
Control/Reference Investigational Product 
Product name: 
Saline solution 
Chemical name: 
Sodium chloride solution (0.9%) 
Molecular formula: 
 
Dosage form: 
3 mL ophthalmic solution 
Unit dose 
 
Route of administration 
Topical ocular administration 
Physical description 
Colorless and clear ophthalmic solution 
Excipients: 
 
Manufacturer: 
 
 
 
5.2 Study Drug Storage 
The study drugs must be stored in a secure area accessible only to the investigator and 
his/her designees. Study drugs must be stored at room temperature and must not be 
refrigerated. The investigational product must be protected from light, and secured at the 
investigational site in a locked container. Subjects should be instructed to store study drug 
in the same manner at home. Subjects should not use dispensed bottle that has been opened 
for more than 30 days. However, this may be prolonged at the discretion of the Investigator 
due to visit schedules. 
Study medication shall be stored under temperature-controlled conditions with accessibility 
only to pharmacy staff and the site pharmacist who is authorized to dispense it to the subject. 
5.3 Study Drug Preparation 
When instructed by the investigator, or designee, the clinical staff will dispense one kit 
containing 2 bottles for each subject on Days 1 and 15 (± 1), and two kits on Day 29 (± 2). 
Subjects will be instructed on appropriate hygiene and eye drop dosing technique for 
multiple use drops by clinic staff. Subjects will self-administer NOV03 or Saline eye drops 
under the supervision of the medication coordinator on Day1 (Visit 1) as shown in 
Appendix 2. The bottles are designed for multiple use.  
5.4 Administration of Study Drug  
On Day 1 the first dose of drops will be instilled by the subject during the first clinic visit. 
During Days 2 through 57 (±2), subjects will be instructed to instill their drops into both 
eyes BID or QID. Clinic staff will coach the subjects to dose themselves at approximately 
the same time every day ± 1 hour. If a dose is missed, then the next dose should be 
administered on time. 


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5.4.1 Dispensation Schedule 
• Study drug will be provided to sites as subject kits containing 2 bottles of 
NOV03 or saline solution. 
• At the end of Visit 1, qualified subjects will be randomized and the first dose 
of study drug will be administered in the study center. The subject will receive 
the first subject kit. Subjects will be instructed to only open one bottle at a time. 
They should be instructed not to discard the empty bottles but return them at 
their next visit. Subjects will record in their diary that their doses were taken.  
• At Visit 2, used/unused study drug will be collected from subjects for drug 
accountability. The subject will be dispensed a new subject kit to continue daily 
dosing. Subjects will be instructed to only open one bottle at a time. They 
should be instructed not to discard the empty bottles but return them at their 
next visit. Subjects will record in their diary that their doses were taken.  
• At Visit 3 used/unused study drug will be collected from subjects for drug 
accountability. Subjects will receive two subject kits. Subjects will be 
instructed to only open one bottle at a time. They should be instructed not to 
discard the empty bottles but return them at their next visit. Subjects will record 
in their diary that their doses were taken.  
• At Visit 4 used/unused study drug will be collected from subjects for drug 
accountability.  
• Subjects will be instructed to immediately contact the site if there is any 
problem with the study drug, e.g. kit/bottle(s) was damaged or lost or if the 
open bottle was dropped. In case the subject needs a replacement, a new kit is 
assigned to the subject. 
5.5 Study Drug Accountability 
All study medication that is used during the course of the study must be accounted for on 
a drug accountability form. Investigational study medication orders, records of receipts, 
dispensing records, and inventory forms will be examined and reconciled. 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 study drug 
cartons (kits and their components) sent to the site, the amount used and unused at the 
time of reconciliation. No investigative drugs or kits will be discarded prior to full 
accountability by Sponsor’s monitor. 
Study drug shipment records will be verified and accountability performed by comparing 
the shipment inventory sheet to the actual quantity of drug bottles received at the site. 
Accurate records of receipt and disposition of the study drug (e.g. dates, quantity, subject 
number, kits used, kits unused, etc.) must be maintained by designated site personnel. 


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5.6 Study Drug Handling and Disposal 
Unless otherwise directed, at the end of the study all unused investigational medications 
must be directly shipped from the clinical site to the disposal facility to dispose of the 
medications. Note: The medications should not be disposed of prior to full 
accountability by the sponsor’s monitor. The clinical site will provide a copy of all 
completed drug disposition forms to the sponsor after the completion of the study. 


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6 STUDY METHODS AND PROCEDURES 
6.1 Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding electronic case report form (eCRF) 
along with the reason the medication was taken. 
Therapies such as lid scrubs, lid wipes, warm compresses, systemic antibiotics had to be 
stable within the last 30 days prior to Visit 1 and should be maintained stable throughout 
the study. 
6.2 Prohibited Medications 
Disallowed medications and treatments are listed in the Exclusion Criteria (Section 3.4). 
All medications and treatments that were not allowed prior to study are also not allowed 
during the study. No dry eye treatment such as artificial tears, gels, or ointments or True 
TearTM device (Intranasal Tear Neurostimulator) shall be used within 24 hours prior to Visit 
1 and through the whole duration of the study. Physical treatments such as lid scrubs, lid 
wipes, warm compresses and systemic antibiotics or oral supplements must be kept 
unchanged.  
Specific prohibitions include: 
• Topical steroids treatments, topical cyclosporine, lifitegrast, serum tears or topical 
anti-glaucoma medication within 60 days prior to Visit 0 
 
 
 
 
6.3 Restrictions and Prohibitions 
 
 
 
 
 
 
 
 
6.4 Examination Procedures 
6.4.1 Procedures to be performed at each study visit with regard to study objective(s) 
See Appendix 1 for a schedule of visits and measurements in recommended order. 
Appendix 3 describes the eye examinations. 
 
 


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Visit 0 (Within 14 days before Visit 1): Screening 
• Informed consent / HIPAA; 
• Demographic data and medical / medication history; 
• Review of inclusion / exclusion criteria;  
• Adverse event query; 
• Blood pressure and heart rate; 
• Ocular Surface Disease Index (OSDI©) questionnaire; 
• Visual acuity; 
• Slit-lamp biomicroscopy; 
• Tear Film Break-up Time (TFBUT); 
• Fluorescein staining cornea (NEI grading); 
• Lissamine green staining conjunctiva (Oxford scale); 
• Meibomian gland assessment (MGD score);  
• Schirmer’s Test I (without anesthesia), 
 
 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Blood sample collected for hematology and serum chemistry, and 
pregnancy test (if applicable); 
• Qualified subjects will be scheduled for Visit 1. 


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Visit 1 (Day 1): Baseline/Randomization 
• Medical/medication history update; 
• Review of inclusion / exclusion criteria; 
• Adverse event query; 
 
 
 
 
 
 
 
 
 
 
 
 
• Visual acuity; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Slit-lamp biomicroscopy; 
 
 
• Fluorescein staining cornea (NEI grading); 
• 
 
 
 
 
 
 
• Randomization; 
• In-office dose of study drug; 
• Blood draw PK; 
o *Procedure at selected sites in a subset of subjects. Samples will 
be taken pre-dose and at 0.5, 1, 2, and 4 hours (±5 min for all 
time points) after instillation. 
• Dispensation of diary and study drug for self-administered dosing 
until Visit 2; 


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o Subjects will be instructed about the frequency of dosing in each 
eye according to their assigned treatment; 
o Subjects will be instructed to dose with study drug on the 
morning of their next visit 
 
 
o Subjects will record their symptoms on their diary each day prior 
to dosing with study drug; 
o Subjects will indicate in the diary that their dose was taken, date 
and time, and number of drops; 
 
Visit 2 (Day 15 ± 1): 2-Week Follow-Up 
• In the beginning of the visit subject will be asked when he/she dosed 
with study drug and the time of the last dose before assessment will 
be collected.
 
 
• Collection and review of study drug and diary; 
• Medical/medication history update; 
• Adverse event query; 
 
 
 
 
 
 
 
 
 
• Visual acuity; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Slit-lamp biomicroscopy; 
 
 
• Fluorescein staining cornea (NEI grading); 
 
 
 
  


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• Dispensation of diary and study drug for self-administered dosing 
until Visit 3; 
o Subjects will be instructed about the frequency of dosing in each 
eye according to their assigned treatment; 
o Subjects will be instructed to dose with study drug on the 
morning of their next visit 
 
 
o Subjects will record their symptoms on their diary each day 
prior to dosing with study drug; 
o Subjects will indicate in the diary that their dose was taken, date 
and time, and number of drops 
 
Visit 3 (Day 29 ± 2): 4-Week Follow-Up 
• In the beginning of the visit subject will be asked when he/she dosed 
with study drug and the time of the last dose before assessment will 
be collected.
 
 
• Collection and review of study drug and diary; 
• Medical/medication history update; 
• Adverse event query; 
 
 
 
 
 
 
 
 
 
• Visual acuity; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• Slit-lamp biomicroscopy; 


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• Fluorescein staining cornea (NEI grading); 
 
 
 
 
 
 
 
• Intraocular pressure; 
• Dispensation of diary and study drug for self-administered dosing 
until Visit 4; 
o Subjects will be instructed about the frequency of dosing in each 
eye according to their assigned treatment; 
o Subjects will be instructed to dose with study drug on the 
morning of their next visit 
 
 
o Subjects will record their symptoms on their diary each day 
prior to dosing with study drug; 
o Subjects will indicate in the diary that their dose was taken, date 
and time, and number of drops 
 
Visit 4 (Day 57 ± 2): 
• In the beginning of the visit subject will be asked when he/she dosed 
with study drug and the time of the last dose before assessment will 
be collected.
 
 
• Collection and review of study drug and diary; 
• Medical/medication history update; 
• Adverse event query; 
• Blood pressure and heart rate; 
 
 
 
 
 
 
 
 
 
 
• Visual acuity; 


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• Slit-lamp biomicroscopy; 
 
 
• Fluorescein staining cornea (NEI grading); 
 
 
 
  
 
 
 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Blood sample collected for hematology and serum chemistry, and 
pregnancy test (if applicable); 
• Blood draw PK (specific sites); 
o In the same subset of subjects at selected sites that participated 
in the Visit 1 PK draw. 
o 1 sample only at the end of the visit 
 
6.4.2 Early Termination/Discontinuation 
If a subject is discontinued from the study prior to Visit 4 (Day 57 ± 2), then all safety 
evaluations should be performed on the day of discontinuation (early termination) or at 
the discretion of the investigator. 
Adverse Events (both elicited and observed) and SAEs will be monitored throughout the 
study. The investigator will promptly review all AEs (both elicited and observed) for 
accuracy and completeness. All AEs will be documented on the appropriate source 
document and case report form. 
If a female reports a pregnancy or has a positive pregnancy test during the study the 
investigator must report the pregnancy and the outcome of the pregnancy to 
 
Product Safety within 24 hours of learning about the pregnancy.  


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A Pregnancy Questionnaire (provided in the Site Procedure Manual) will be completed by 
the study site’s Principal Investigator. The Pregnancy Questionnaire will be sent to 
 Product Safety via the SAE Fax number
. The 
 Drug Safety 
Associate will forward the documentation to the Medical Monitor and the sponsor for 
review.   
At the completion of the pregnancy, the Pregnancy Outcome form (provided in the Site 
Procedure Manual) is to be submitted to the 
Product Safety Associate via the SAE 
fax number 
. The 
 Product Safety Associate will manage the query 
and reconciliation process until the pregnancy documentation is complete. 
6.4.3 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures performed 
at an unscheduled visit will be recorded in the source documents and on the Unscheduled 
Visit eCRF pages. Any procedure indicated in the eCRF that is not performed should be 
indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Visual acuity; 
• Slit-lamp biomicroscopy; 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Safety blood draws; 
• Pregnancy test; 
• PK samples (at selected sites) 
• Assessment of AEs; 
• Assessment of concomitant medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 
 
6.4.4 Pharmacokinetic Samples 
Samples for PK analysis will be collected at the scheduled time points (pre-dose and at 0.5, 
1, 2, and 4 hours [±5 min for all time points] after instillation) at Visit 1. At Visit 4 and 
unscheduled visits, PK samples should only be taken once. The sample volumes are 
described in Section 9.8. Date and time of specified dose and date and actual PK sampling 
times will be recorded in the eCRF. 
Samples will be processed, transferred to, and stored at the corresponding bioanalytical 
laboratory during the course of the study. This process will be detailed in a separate 
laboratory manual. After completion of the study, all samples will be destroyed after 
analysis or at the discretion of the sponsor. 


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6.5 Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of study drug at the end of 
Visits 0, 1, 2, and 3, and given written instructions (Appendix 2). The used and unused 
study drug bottles will be collected and counted at each visit from Visit 1 up to and 
including Visit 4 to assess dosing. 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.  
 
 
 
 
6.6 Subject Disposition 
6.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
6.6.2 Discontinued subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• Adverse events; 
• Protocol violations; 
• Administrative reasons (e.g. inability to continue, lost to follow up); 
• Sponsor termination of study; 
• Subject choice (e.g. withdrawal of consent);  
• Other 
Note: In addition, any subject may be discontinued for any sound medical reason at the 
discretion of the investigator. 
Notification of a subject discontinuation and the reason for discontinuation will be made to 
the CRO and/or study sponsor and will be clearly documented on the eCRF. 
Discontinued subjects will not be replaced. 
6.7 Study 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 study drug, e.g. due 
to: 
• Occurrence of significant previously unknown adverse reactions or unexpectedly 
high intensity or incidence of known adverse reactions, or 
• Other unfavorable safety findings. 
Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical 
reasons. 


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Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely. 
Discontinuation of development of the sponsor’s investigational product. 
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. 
The whole trial may be terminated or suspended upon request of Health Authorities. 
6.8 Study Duration 
An individual subject’s participation will involve 4 visits over approximately a 10-week 
period, including screening. After the study, subjects will be treated according to standard 
of care, as needed. The total duration of the study from first subject in to last subject out is 
expected to be 24 weeks (6 months).   
6.9 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to review 
protocol compliance, assess study drug accountability, subject safety, and ensure the study 
is being conducted according to the pertinent regulatory requirements. The review of the 
subjects’ medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring plan. 
Domestic and foreign regulatory agencies, 
 Product Safety (Clinical Research 
Organization [CRO]) 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 giving consideration to data protection as well as subject 
confidentiality to the extent that local, state, and federal laws apply. 


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7 ADVERSE EVENTS 
7.1 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 (eg, an abnormal laboratory finding), 
symptom, or disease occurring after the subject signed Informed Consent Form (ICF)  
without any judgment about causality.   
If there is a worsening of a medical condition that was present prior to the administration 
of the study drug, this should also be considered a new AE and reported. Any medical 
condition present prior to the administration of the study drug that remains unchanged or 
improved should not be recorded as an AE at subsequent visits. 
Worsening of Dry Eye Disease 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 decrease (defined as an increase of 0.22 or greater in 
logMAR score) from baseline (Visit 0) will be considered an Adverse Event. 
Study drug includes the investigational drug under evaluation and any comparator drug, 
placebo, or any other medications required by the protocol given during any stage of the 
study. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to study drug, action(s) taken, seriousness, and outcome of any sign 
or symptom observed by the physician or reported by the subject upon indirect questioning. 
7.1.1 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 patient/subject. The 
assessment of severity is made irrespective of relationship to study drug or seriousness of 
the event and should be evaluated according to the following scale: 
• 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. 
7.1.2 Relationship to Study Drug 
The relationship of each AE to the investigational product should be determined by the 
investigator using these explanations: 


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• 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 IP exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome); one or more occurrences of an event that is not commonly associated 
with IP exposure, but is otherwise uncommon in the population exposed to the IP (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 study population independent of drug therapy) that 
indicates those events occur more frequently in the IP-treatment group than in a concurrent 
or historical control group. 
7.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the study drugs. 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 that is unrelated to the study drug. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
7.2 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; 
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. 
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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. 
Note:  The term “prolongation of existing hospitalization” refers to any 
extension of an inpatient hospitalization beyond the stay anticipated or required 
for the reason for the initial admission as determined by the investigator or 
treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note:  A serious adverse event (SAE) specifically related to visual threat would 
be interpreted as any potential impairment or damage to the subject’s eyes (e.g. 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 
• A congenital anomaly/birth defect. 
• 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 patient or 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. 
7.3 Procedures for Reporting Serious Adverse Events 
Using the SAE Report Form approved for this study, all SAEs and their outcomes must be 
reported to 
 Product Safety (who will notify the Medical Monitor and the study 
sponsor). 
7.3.1 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the study drug, must be 
immediately (i.e. within a maximum 24 HOURS after becoming aware of the event) 
reported to 
 Product Safety. The 
 Product Safety Associate will forward the 
documentation to the Medical Monitor and the sponsor for review. Within 24 hours of 
knowledge of a new SAE, the investigator must enter the SAE information onto the hard 
copy SAE report form and transmit the form to the SAE Fax number below. The 
investigator must verify the report was received by 
Product Safety. If the 
investigator is not able to successfully fax the SAE Report or verify it was successfully 


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received by 
 Product Safety, the investigator must call the 
 SAE Hot Line to 
report the SAE and follow-up with the 
 Product Safety Associate by phone 
 
 or email 
  
 
SAE Fax Number (US):
 
SAE Hot Line Number (US): 
 
 
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 study ID number 
● Description of the Serious Adverse Event 
● Date of the Serious Adverse Event  
● Criterion for seriousness 
● Preliminary assignment of causality to study drug 
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 
 
Product Safety, 
 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 
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 
 Product Safety and the study 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 study drug; and inform the IRB of the AE within 
their guidelines for reporting SAEs. 
All SAEs will be reported from the start of the study product. All SAEs will be followed 
until resolution, stabilization, the event is otherwise, explained, or the subject is lost to 
follow-up. 
7.3.2 Reporting a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
All SAEs that are ‘suspected’ (relationship to drug of definite, probable or possible) and 
‘unexpected’ are to be reported to 
 Product Safety 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 
(eg, United State Food and Drug Administration [FDA]) as required by the IRB/IEC, 
federal, state, and local regulations and timelines. 


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7.4 Procedures for Unmasking of Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study 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 study treatment assignment from the Interactive Web Response System (IWRS). 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 7.3.1). 
In a non-emergency situation, when a code break is required, it must be discussed with the 
Medical monitor and/or 
 Product Safety and the study 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 study and should complete both the Early Termination 
and Follow-up procedures. 
Study staff will examine and reconcile study medication orders, records of receipts, 
dispensing records, and inventory forms throughout the study (see Section 9.5.2). 
7.5 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.  
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 
Product Safety 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. 


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8 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
8.1 Analysis Populations 
The following analysis populations will be considered: 
• All Subjects – All subjects who sign the ICF 
• Modified Intention-to-Treat – Modified Intention-to-Treat (mITT) includes all 
subjects randomly assigned to study treatment and who take at least 1 dose of 
study treatment. Subjects will be analyzed according to the treatment they are 
randomized to. 
• Per Protocol Population – The Per Protocol (PP) population includes subjects in 
the safety population who do not have significant protocol deviations and who 
complete the study. Protocol deviations will be assessed prior to database lock 
and unmasking. The PP population will be analyzed using observed data only 
for efficacy variables. Subjects in the PP population will be analyzed as treated. 
• Safety Population – The safety population includes all subjects who have 
received at least one dose of the investigational product. The safety population 
will be analyzed for all safety assessments. Subjects in the Safety population 
will be analyzed as treated.  
• PK Population – The PK population includes all subjects with an evaluable PK 
sample. The PK population will be used to summarize all perfluorohexyloctane 
blood concentrations. 
The statistical analysis of safety data will be performed for the safety population. The 
analysis of efficacy data will primarily be performed for the mITT population. The 
efficacy analysis based on the PP population will serve as the sensitivity analyses. 
8.2 Statistical Hypotheses 
The following two sets of hypotheses will be tested as the primary hypotheses of the study: 
H01: The difference in the mean change from baseline to Week 8 total Corneal Fluorescein 
Staining (CFS) score between NOV03 QID and combined saline solution groups (NOV03 
QID – combined saline solution) = 0 against 
H11: The difference in the mean change from baseline to Week 8 total CFS score between 
NOV03 QID and combined saline solution groups (NOV03 QID – combined saline 
solution) ≠ 0 
and 


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H02: The difference in the mean change from baseline to Week 8 total CFS score between 
NOV03 BID and combined saline solution groups (NOV03 BID – combined saline 
solution) = 0 against 
H12: The difference in the mean change from baseline to Week 8 total CFS score between 
NOV03 BID and combined saline solution groups (NOV03 BID – combined saline 
solution) ≠ 0. 
8.3  Sample Size 
This study is expected to enroll 100 subjects in each of the four treatment arms, for a total 
of 300 randomized subjects. 
 
 
 this study has 88% power to detect a difference of 
0.8 units in the change from baseline in corneal staining between an active arm and the 
combined control arm using a one-sided t-test at 5% level of significance. This assumes a 
standard deviation of 1.9 units for each arm. 
8.4 Statistical Analysis 
8.4.1 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, with placebo presented both pooled 
as well as separately for QID and BID dosing. 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 
 will be one-sided at a significance level of 0.05. 
8.4.2 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. 


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8.4.3 Missing Data 
The primary efficacy analyses will be performed using the mITT population, and using a 
repeated measures model without any imputation for missing observations. Sensitivity 
analyses using different analysis populations and methods for handling missing data may 
be further detailed in the Statistical Analysis Plan (SAP). 
 
 
8.4.4 Multiplicity Consideration 
To control for inflation of type 1 error rate due to multiple hypotheses, the analysis will be 
conducted in a hierarchical manner. 
The hypothesis testing to compare the BID arm and control will only proceed if the QID 
vs. control comparisons are statistically significant. 
8.4.5 Primary Efficacy Analyses 
All efficacy analyses will be primarily based on the mITT. Population. Analyses based on 
Per-Protocol (PP) population will be supportive in nature. The primary evaluation of 
efficacy of the active arms will be against a combined control arm (with BID and QID saline 
solution). Analyses will also be provided comparing BID to QID saline solution to 
determine appropriateness of combining for the primary analysis. Sensitivity analysis may 
be undertaken for dosing-regimen matching control (that is, QID active vs. QID saline 
solution). 
The primary analysis will be performed to compare the Week 8 difference in the change 
from baseline in total CFS between each of the active NOV03 groups and the combined 
saline solution group. The comparison will be conducted using a repeated measures model 
with treatment, site, visit, and treatment by visit interaction as fixed categorical factors, 
baseline as a continuous covariate, and using an unstructured covariance matrix. To 
establish evidence of efficacy in this proof of concept study, the hypothesis tests will be 
one-sided and performed at the 0.05 significance level. 
 
The total CFS score is calculated as the sum of the staining from the inferior, central, 
superior, nasal, and temporal regions, such that a larger number indicates worse dry eye 
signs.  
Treatment group contrasts and least-squared (LS) means will be presented from the model 
together with two-sided 95% confidence intervals.  
The primary analysis will use the mITT population at the Visit 4, Week 8 visit; the PP 
population will also be used to further understand the primary results. 
 
 
 
 


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8.4.7 Safety Variables 
All safety analyses will be performed on the Safety Population. The primary evaluation of 
safety of the active arms will be against a combined control arm (with BID and QID saline 
solution). The summaries of the safety data will be presented for a combined control arm 
as well as for each control arm separately. Additionally, the listings will have an indicator 
for subjects receiving BID or QID saline solution. 
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 study drug 
discontinuation will also be summarized by treatment received. 
Analysis of Adverse Events 
Adverse events 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 group. An AE is treatment 
emergent if it occurs or worsens after the first dose of study 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, 


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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 and 
summarized by treatment group. 
Analysis of Laboratory Parameters 
Clinical laboratory parameters including hematology and serum chemistry will be 
summarized by treatment group and by visit. Baseline values, the values at each subsequent 
visit, and changes from baseline will be summarized for each of the quantitative laboratory 
assessments by treatment. Shift tables of chemistry and hematology, results will be used to 
summarize changes from baseline to study termination (or early termination). The number 
and percentage of chemistry and hematology values outside of normal ranges and/or with 
potential clinical importance will be summarized by visit and treatment. 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, dilated 
fundoscopy, safety laboratory, and intraocular pressure will be summarized by treatment 
group and visit using descriptive statistics. Changes or shifts from baseline will also be 
summarized where appropriate. For assessments performed by eye, study eye and fellow 
eye will be summarized separately. In addition, shifts from baseline to worst on-treatment 
value for ocular safety assessments will be summarized. 
8.4.8 Pharmacokinetic Variables 
Whole blood for perfluorohexyloctane blood concentration measurements will be drawn 
from a minimum of 66 subjects at one or more investigational sites with the goal of having 
samples from 20 subjects per each of the active treatment arms. Blood concentrations of 
perfluorohexyloctane will be summarized descriptively. The following PK parameters will 
be estimated: AUC0-, Cmax, tmax.  
The relationship between safety endpoints and pharmacokinetic endpoints may be explored 
to understand the impact of PK parameters on safety. 
Interim Analyses 
No interim analyses are planned for this study. 
 
 


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9 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study 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 study drugs in the countries involved 
will be adhered to. 
9.1 Protection of Human Subjects 
9.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject prior to 
enrollment into the study. 
All informed consent/assent forms must be approved for use by the sponsor and receive 
approval from an IRB/IEC prior to their use. If the consent form requires revision (eg, 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 study as well as those currently enrolled in the study. 
9.1.2 Institutional Review Board (IRB) Approval 
This study 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. 
9.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated with 
the Declaration of Helsinki. 
9.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should 
be maintained by the investigator and his/her staff with adequate precautions as to ensure 
that the confidentiality of the data in accordance with local, state, and federal laws and 
regulations. 
Monitors, auditors and other authorized representatives of WCCT Product Safety, the 
sponsor, the IRB/IEC approving this study, the FDA, the Department of Health and Human 
Services, other domestic government agencies, and other foreign regulatory agencies will 
be granted direct access to the study subject’s original medical and study records for 
verification of the data and/or clinical trial procedures. Access to this information will be 
permitted to the aforementioned individuals to the extent permitted by law. 


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A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
subject’s identity will not be disclosed in these documents. 
9.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and EKGs. The investigator’s electronic copy of the Case Report 
Forms serves as the investigator’s record of a subject’s study-related data. 
9.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the distribution 
and use of all study drug 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 study drug. 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 study 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 study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
9.5 Labeling, Packaging, Accountability, and Return or Disposal of 
Study Drug 
9.5.1 Labeling/Packaging 
Investigational drug 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 5.4.1 for details regarding dispensation to subjects. 
It should be noted that the pharmacist is also masked when dispensing study drug. The 
label will contain the following information: 
As per the Code of Federal Regulations 21 part 312, section 312.6, the labels shall be 
comprised of: 
 
• Protocol number 
• Investigational new drug statement 
• Lot number 


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• Storage conditions 
• Name and address of the Sponsor 
 
9.5.2 Accountability of Study Drug 
The study drugs are only to be prescribed by the principal investigator or his/her named sub 
investigator(s), and are only to be used in accordance with this protocol. The study drugs 
must only be distributed to subjects properly qualified under this protocol to receive study 
drug. The investigator must keep an accurate accounting of the study drugs by maintaining 
a detailed inventory. This includes the amount of study drugs received by the site, amount 
dispensed to subjects, amount returned to the site by the subjects, and the amount returned 
to the sponsor upon the completion of the study 
9.5.3 Return or Disposal of Study Drug 
All study drugs will be returned to the sponsor or their designee for destruction. 
9.6 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 transcribed 
to the eCRFs. The investigator is responsible for ensuring that study data is completely and 
accurately recorded on each subject’s eCRF, source documents, and all study-related 
materials. All study 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 (eg, by drawing a single line through the incorrect entry 
and writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
Data entry of all enrolled and randomized subjects will use software that conforms to 21 
CFR Part 11 requirements, and will be performed only by staff that have been trained on 
the system and have access to the system. Data will not be entered for screen failure 
subjects. An audit trail will be maintained within the electronic system to capture all 
changes made within the eCRF database. After the end of the study and database lock, 
compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be provided 
to each investigator site to be maintained on file by the investigator. 
9.7 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved 
in the study. Authorship will be established before writing the manuscript. The study 
sponsor will have the final decision regarding authorship, manuscript and publication. 


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9.8 Handling of Biological Specimens 
Blood samples will be collected for hematology (2 mL per draw), serum chemistry (5 mL 
per draw), pharmacokinetics (2 mL per draw), and pregnancy tests (if applicable, taken 
from 5 mL of serum). The approximate collection amounts per visit are described in Table 
4: 
Table 4. 
Blood Volumes for Safety Laboratory Tests and Pharmacokinetics 
Approximate Blood Collection Amounts per Visit 
 
Visit 0 
Visit 1 
Visit 4 
Hematology 
2mL 
N/A 
2mL 
Serum Chemistry 
5mL 
N/A 
5mL 
PK 
N/A 
10mL 
2mL 
Total 
7mL 
10mL 
9mL 
• If blood samples are collected via an indwelling cannula, an appropriate amount 
(ie, 1 mL) of fluid slightly greater than the dead space volume of the lock will 
be removed from the cannula and discarded before each blood sample is taken. 
After blood sample collection, the cannula will be flushed with saline or sodium 
heparin of 10 U/mL and charged with a volume equal to the dead space volume 
of the lock. 
• If subject is a female of childbearing potential, a serum pregnancy test will be 
taken. 
• Pharmacokinetics testing for perfluorohexyloctane at selected sites only.  
 
Clinical laboratory tests are listed in Table 5. 


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Table 5. Clinical Laboratory Tests 
Hematology 
Serum Chemistry                          Pregnancy 
Platelet count 
Alanine aminotransferase (ALT)            Serum β- HCG 
Red blood cell (RBC) count  
Albumin 
Hemoglobin (Hb) 
Alkaline phosphatase (ALP) 
Hematocrit (Hct)  
Aspartate aminotransferase (AST) 
Mean cell volume (MCV) 
Total bilirubin (T-Bil) 
Mean cell hemoglobin (MCH) 
Blood urea nitrogen (BUN) 
Mean cell hemoglobin 
concentration (MCHC) 
Calcium 
Chloride 
Reticulocytes 
Total cholesterol  
WBC count (with differential)  
Creatinine 
Neutrophil 
Creatine kinase (CK) 
Lymphocyte 
Gamma-glutamyl transpeptidase (GGT) 
Monocyte 
Total protein (TP) Albumin:Globulin ratio 
Eosinophil 
Glucose 
Basophil 
Lactic dehydrogenase (LDH) 
 
Phosphorus 
 
Sodium 
 
Potassium 
Magnesium 
 
Total protein (TP) 
 
Triglycerides 
 
Uric acid 
 
Bicarbonate 
 
Globulin 
 
low density lipoprotein (LDL) 
 
high density lipoprotein (HDL) 
 
 
 
 


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