Clinical trial NCT04140227
Conditions: Dry Eye Disease (DED)
Sponsor: Bausch & Lomb Incorporated
Start date: 2020-09-24; Completion date: 2022-01-05
Enrollment: 256 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objectives of this trial are to evaluate the safety and tolerability of perfluorohexyloctane (NOV03) ophthalmic solution during long-term use in subjects with Dry Eye Disease (DED) associated with MGD (Meibomian Gland Dysfunction).

Further objective is to evaluate the efficacy of perfluorohexyloctane (NOV03) solution during long-term use in subjects with DED associated with MGD.

Detailed description:
The objectives of this trial are to evaluate the safety and tolerability of perfluorohexyloctane (NOV03) ophthalmic solution during long-term use in subjects with Dry Eye Disease (DED) associated with MGD (Meibomian Gland Dysfunction).

Further objective is to evaluate the efficacy of perfluorohexyloctane (NOV03) solution during long-term use in subjects with DED associated with MGD.

Arms: arm 1: 100% Perfluorohexyloctance solution 4 times daily (QID)
Interventions: intervention 1: NOV03
Intervention descriptions: intervention 1: 100% Perfluorohexyloctane

Protocol documents:
Prot_SAP_000.pdf: 
NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb, Inc. 
Clinical Trial Protocol # NVU-004 
12 March 2020 FINAL v3.0  
 
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Clinical Trial Protocol 
 
Protocol Title: 
A Phase 3, Multi-Center, Open-Label Extension (OLE) 
Clinical Trial to Assess the Extended Long-Term Safety 
and Tolerability of NOV03 (Perfluorohexyloctane) in 
Subjects who Completed Trial NVU-003 (Kalahari OLE) 
Protocol Number: 
NVU-004 
Trial Phase: 
3 
Investigational 
Product 
Name: 
NOV03 (100% perfluorohexyloctane) 
IND Number: 
IND 130558 
Indication: 
Dry Eye Disease (keratoconjunctivitis sicca) associated 
with Meibomian Gland Dysfunction  
Investigators: 
Multi-Center 
Sponsor: 
Bausch & Lomb, Incorporated  
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
USA 
Clinical Research 
Organization: 
Lexitas Pharma Services, Inc 
313 Foster St. 
Durham, NC 27701 
USA 
IRB/IEC: 
Sterling IRB 
6300 Powers Ferry Rd 
Suite 600-351 
Atlanta, GA 30339 
Version: 
3.0 
Amendment 2 
12 MAR 2020 
Amendment 1 
13 DEC 2019 
Original Protocol Date: 
14 OCT 2019 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Bausch & Lomb, Inc. 
Further dissemination, distribution or copying of this protocol or its contents is strictly 
prohibited. 
Regulatory Statement 
This trial will be performed in compliance with the protocol and in accordance with Good 
Clinical Practice (International Conference on Harmonisation [ICH], Guidance E6), 


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principles of human subject protection, and applicable country-specific regulatory 
requirements. 
1 SYNOPSIS AND TRIAL CONTACT INFORMATION 
 
1.1 TRIAL CONTACT INFORMATION 
SPONSOR PERSONNEL 
Exc. Director - Clinical Affairs  
Jason Vittitow, PhD 
Tel: 908-541-3060 
Jason.Vittitow@bausch.com 
Sr. Clinical Trial Manager 
Dan Donatello 
Tel: 585-338-5306 
Daniel.donatello@bausch.com 
MEDICAL MONITOR 
Medical Monitor 
Kenneth Sall, MD 
Tel: 562-754-2947 
Cell (24-Hr Line): 562-754-2947 
Fax: 714-960-5434 
drsall@sallresearch.com 
Clinical Research Organisation (CRO) PERSONNEL 
Clinical Project Manager: 
Nicole Derthick 
Tel: 919-699-9629 
Fax: 919-640-1663 
Nicole.Derthick@Lexitas.com 
Biostatistician: 
Emily Woolley, M.Sc. Statistics 
Tel: 206-577-0273 
Fax: 206-547-4671 
emilyw@axioresearch.com 
 
 
 


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1.2 SYNOPSIS 
Protocol Title: 
A Phase 3, Multi-Center, Open-Label Extension 
(OLE) Clinical Trial to Assess the Extended Long-
Term 
Safety 
and 
Tolerability 
of 
NOV03 
(Perfluorohexyloctane) in Subjects who Completed 
Trial NVU-003 (Kalahari OLE) 
Protocol Number: 
NVU-004 
Investigational Medicinal 
Product: 
NOV03 (100% perfluorohexyloctane) 
Trial Phase: 
3 
Trial Objective: 
The primary objectives of this trial are to evaluate 
the safety and tolerability of perfluorohexyloctane 
(NOV03) ophthalmic solution during long-term use 
in subjects with Dry Eye Disease (DED) associated 
with MGD (Meibomian Gland Dysfunction).  
The other objective is to evaluate the efficacy of 
perfluorohexyloctane (NOV03) solution during 
long-term use in subjects with DED associated with 
MGD. 
Overall Trial Design 
 
Structure: 
Open-label, multicenter, single-arm 
Participant Duration: 
Approximately 52 weeks. 
Trial Duration: 
The estimated trial duration is 18 months, from first 
subject first visit (FSFV) until last subject last visit 
(LSLV). 
Dosage/Dose Regimen: 
Subjects who completed trial NVU-003 and meet all 
of the inclusion and none of the exclusion criteria 
will receive the following bilateral ophthalmologic 
treatment beginning with Visit 1 and ending with 
Visit 6. 
1) NOV03 (100% perfluorohexyloctane) 4 times 
daily (QID). 
Summary of Visit Schedule: 
6 visits over the course of approximately 52 weeks 
 
• Visit 1 = Day 1, open label treatment start 
(= Day 57 of NVU-003 trial) 
• Visit 2 = week 4 ± 2 days, 
• Visit 3 = week 12 ± 7 days, 
• Visit 4 = week 26 ± 7 days, 
• Visit 5 = week 40 ± 7 days, 
• Visit 6= week 52 ± 7 days 
 


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7 telephone calls (TC; optionally onsite visits) 
• TC 1= week 8 follow-up ± 2 days 
• TC 2 = week 16 follow-up ± 7 days 
• TC 3 = week 22 follow-up ± 7 days 
• TC 4 = week 30 follow-up ± 7 days 
• TC 5 = week 36 follow-up ± 7 days 
• TC 6 = week 44 follow-up ± 7 days 
• TC 7 = week 48 follow-up ± 7 days 
Measures Taken to Reduce 
Bias: 
• Subjects shall be instructed not to discuss 
investigational medicinal product (IMP) 
characteristics and/or their experience with 
the IMP with other trial participants. 
• Follow-up NVU-004 subject visits should not 
be scheduled for the same day as NVU-003 
subject visits at a given site to prevent 
unblinding of NVU-003. 
• If NVU-003 and NVU-004 subjects are 
present at the clinical site at the same time, the 
site should take precautions to prevent 
subjects from interacting. 
Trial Population Characteristics 
Number of Subjects: 
Approximately 200 subjects who completed trial 
NVU-003 will be enrolled at up to 20 clinical sites. 
Condition/Disease: 
Dry Eye Disease (keratoconjunctivitis sicca) 
associated with Meibomian Gland Dysfunction 
Inclusion Criteria: 
Subjects must: 
1. Have completed trial NVU-003 without major 
protocol deviations, and have been compliant 
with NVU-003 trial procedures and application 
of IMP.   
2. Have a subject reported history of DED in both 
eyes for at least 6 months prior to Visit 0 of 
NVU-003 and be diagnosed with DED at Visit 1 
of NVU-003. 
3. Provide written informed consent.  
4. Be able and willing to follow instructions, 
including participation in all trial assessments 
and visits. 
Exclusion Criteria: 
Subjects must not: 
1. Have permanently discontinued IMP during 
NVU-003 for any reason. 
2. Have any clinically significant ocular surface 
slit-lamp findings at Visit 1 and/or in the opinion 


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of the investigator have any findings that may 
interfere with trial parameters.  
3. Have an ocular or periocular malignancy. 
4. Have a history of herpetic keratitis. 
5. Have any planned ocular and/or lid surgeries 
over the trial period. 
6. Be a woman who is pregnant or planning a 
pregnancy. 
7. Be unwilling to submit to a urine pregnancy test 
at Visit 2, 3, 4, 5 and Visit 6 (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). 
8. Be a woman of childbearing potential who is not 
using an acceptable means of birth control; 
acceptable methods of contraception include: 
hormonal – oral, implantable, injectable, or 
transdermal 
contraceptives; 
mechanical 
– 
spermicide in conjunction with a barrier such as 
a diaphragm or condom; intrauterine device 
(IUD); or surgical sterilization of partner. For 
non-sexually active females, abstinence may be 
regarded as an adequate method of birth control; 
however, if the subject becomes sexually active 
during the trial, she must agree to use adequate 
birth control as defined above for the remainder 
of the trial. 
9. Have a known allergy and/or sensitivity to the 
IMP.  
10. Be currently enrolled in an investigational drug 
or device trial other than NVU-003 or NVU-004. 
11. Have corrected visual acuity worse than or equal 
to logarithm of the minimum angle of resolution 
(logMAR), +0.7 as assessed by Early Treatment 
of Diabetic Retinopathy Study (ETDRS) scale in 
both eyes at Visit 1. 
12. Have a condition or be in a situation which the 
investigator feels may put the subject at 
significant risk, may confound the trial results, 
or may interfere significantly with the subject’s 
participation in the trial. 
Trial Formulations: 
• 100% Perfluorohexyloctane  
Evaluation Criteria 
 


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Efficacy 
and 
Safety 
Endpoint(s):  
Primary Safety Endpoints: 
1. Ocular and non-ocular adverse events 
 
Secondary Safety Endpoints: 
1. Visual acuity (BCVA using ETDRS) 
2. Slit-Lamp biomicroscopy 
3. Intraocular pressure 
4. Dilated fundoscopy 
 
Other Pre-specified Efficacy Endpoints: 
1. CFB of Dryness Score (VAS) to each measured 
post-baseline visit. 
2. CFB in tCFS (NEI scale) to each measured post-
baseline visit. 
3. CFB in CFS sub-regions (NEI scale) to each 
measured post-baseline visit. 
4. Proportion of tCFS responders (≥3 improvement 
based on NEI scale) at each measured post-
baseline visit.  
5. Proportion of Dryness Score responders (≥30 % 
improvement from baseline) at each measured 
post-baseline visit. 
6. Proportion 
of 
cCFS 
responders 
(≥1 
improvement based on NEI scale) at each 
measured post-baseline visit.  
7. CFB 
in 
Visual 
Analogue 
Scale 
(VAS) 
burning/stinging, sticky feeling, foreign body 
sensation, itching, blurred vision, sensitivity to 
light, pain, frequency of dryness, and awareness 
of dry eye symptoms (VAS)  at each measured 
post-baseline visit. 
8. CFB in Ocular Surface Disease Index (OSDI©) 
at each measured post-baseline visit. 
Exploratory Endpoints: 
1. Meibomian Gland Assessment (MGD score) at 
each measured post-baseline visit. 
2. Schirmer’s Test I (without anesthesia) at each 
measured post-baseline visit.  
3. TFBUT at each measured post-baseline visit. 
Other 
Eyedrop Comfort and Acceptability Questionnaire 
General Statistical Methods and Types of Analyses 
Sample Size 
Approximately 200 subjects will be enrolled in order to ensure that at least 100 
evaluable subjects complete the week 26 (6 month) treatment period and at least 100 
evaluable subjects complete the week 52 (12 month) treatment period. 


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With 100 subjects completing the week 52 (or week 26) treatment period, the study 
will have 95% or greater chance of observing adverse events that occur at a true 
incident rate of 3.0% or higher.  
 
Primary Safety Analyses 
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 as received in NVU-003 and overall. An AE is treatment emergent if it occurs or 
worsens after first dose of trial treatment in NVU-004.  
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 provided for ocular and non-ocular AEs. Ocular AEs will 
be summarized at the subject level, at the eye level, and separately for study and fellow 
eyes.  
 
Secondary Safety Analyses 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, dilated 
fundoscopy, and intraocular pressure will be summarized by visit using descriptive 
statistics by treatment group as assigned in NVU-003 and overall. For assessments 
performed by eye, study eye and fellow eye will be summarized separately. Changes 
or shifts from baseline (baseline as defined in NVU-003) will be summarized where 
appropriate. 
 
Further Analyses  
Quantitative other pre-specified efficacy endpoints will be summarized descriptively 
(n, mean, standard deviation, median, min and max) by visit and treatments group as 
assigned in NVU-003 and overall. Changes from baseline (as defined in NVU-003) 
will also be summarized. Assessments performed by eye, study eye and fellow eye will 
be summarized separately.  
Dichotomous other pre-specified efficacy endpoints will be summarized descriptively 
(frequency and percentage). 


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TABLE OF CONTENTS 
 
1 
SYNOPSIS AND TRIAL CONTACT INFORMATION ...................................... 2 
1.1 
TRIAL CONTACT INFORMATION .................................................................. 2 
1.2 
SYNOPSIS ............................................................................................................... 3 
TABLE OF CONTENTS .................................................................................................. 8 
LIST OF ABBREVIATIONS ......................................................................................... 12 
2 
INTRODUCTION .................................................................................................. 14 
2.1 
Dry Eye Disease (DED) ......................................................................................... 14 
2.2 
Product Rationale .................................................................................................. 14 
2.3 
Trial Rationale ....................................................................................................... 15 
3 
TRIAL OBJECTIVES ........................................................................................... 16 
3.1 
Primary Objective ................................................................................................. 16 
3.2 
Secondary Objectives ............................................................................................ 16 
4 
TRIAL DESIGN ..................................................................................................... 16 
4.1 
Overall Trial Design .............................................................................................. 16 
4.2 
End of Trial Definition ......................................................................................... 16 
4.3 
Visit Description and Telephone Calls ................................................................ 16 
4.4 
Trial Flow ............................................................................................................... 18 
4.5 
Enrollment and Treatment Assignment ............................................................. 18 
4.6 
Justification of Trial Design ................................................................................. 18 
4.7 
Justification of Dose .............................................................................................. 18 
5 
TRIAL POPULATION .......................................................................................... 19 
5.1 
Number of Subjects (approximate) ..................................................................... 19 
5.2 
Trial population characteristics ........................................................................... 19 
5.3 
Inclusion Criteria .................................................................................................. 19 
5.4 
Exclusion Criteria ................................................................................................. 19 
5.5 
Subject/Trial Withdrawal Criteria ...................................................................... 20 
6 
TRIAL PARAMETERS ......................................................................................... 21 
6.1 
Primary Endpoints ................................................................................................ 21 
6.2 
Secondary Endpoints ............................................................................................ 21 
6.3 
Exploratory Endpoints ......................................................................................... 22 
6.4 
Other Endpoints .................................................................................................... 22 
7 
TRIAL MATERIALS ............................................................................................ 22 
7.1 
Investigational Medicinal Product ...................................................................... 22 
7.1.1 
IMP(s)/ Formulation ......................................................................... 22 
7.1.2 
Labeling and Packaging of IMP ....................................................... 22 
7.1.3 
IMP Storage ...................................................................................... 23 
7.1.4 
IMP Dispensation ............................................................................. 23 
7.1.5 
Instructions for Use and Administration .......................................... 23 
7.2 
IMP Accountability ............................................................................................... 24 
7.3 
IMP Handling and Disposal ................................................................................. 24 
7.4 
Other Trial Supplies ............................................................................................. 25 
8 
TRIAL METHODS AND PROCEDURES .......................................................... 26 
8.1 
Concurrent Medications and Therapies ............................................................. 26 


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8.2 
Prohibited Medications/ Treatments ................................................................... 26 
8.3 
Restrictions and Prohibitions ............................................................................... 26 
8.4 
Examination Procedures ...................................................................................... 27 
8.4.1 
Procedures to be performed at each trial visit with regard to trial 
objective(s) ..................................................................................................... 27 
8.4.2 
Early Termination/Discontinuation .................................................. 29 
8.4.3 
Unscheduled Visits ........................................................................... 29 
8.5 
Compliance with Protocol .................................................................................... 30 
8.6 
Subject Disposition ................................................................................................ 30 
8.6.1 
Completed Subjects .......................................................................... 30 
8.6.2 
Discontinued subjects ....................................................................... 30 
8.7 
Trial Termination ................................................................................................. 30 
8.8 
Trial Duration ....................................................................................................... 31 
9 
ADVERSE EVENTS .............................................................................................. 32 
9.1 
Adverse Event ........................................................................................................ 32 
9.1.1 
Severity ............................................................................................. 32 
9.1.2 
Relationship to Investigational Product ............................................ 33 
9.1.3 
Expectedness .................................................................................... 33 
9.1.4 
Outcome ............................................................................................ 33 
9.2 
Serious Adverse Events ........................................................................................ 34 
9.3 
Procedures for Reporting Adverse Events and Serious Adverse Events ......... 35 
9.3.1 
Reporting a Serious Adverse Event .................................................. 35 
9.3.2 
Reporting a Suspected Unexpected Serious Adverse Reaction 
(SUSAR) ........................................................................................................ 36 
9.4 
Procedures for Unmasking of IMP ...................................................................... 36 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ........... 36 
9.6 
Reporting Pregnancies .......................................................................................... 36 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ............... 38 
10.1 Analysis Populations ............................................................................................. 38 
10.2 Statistical Hypotheses ........................................................................................... 38 
10.3 Sample Size ............................................................................................................ 38 
10.4 Statistical Analysis ................................................................................................ 38 
10.4.1 General Considerations ..................................................................... 38 
10.4.2 Unit of Analysis ................................................................................ 39 
10.4.3 Missing Data ..................................................................................... 39 
10.4.4 Multiplicity Considerations .............................................................. 39 
10.4.5 Primary Safety Analyses .................................................................. 39 
10.4.6 Secondary Safety Analyses .............................................................. 40 
10.4.7 Other Pre-specified Efficacy Analyses ............................................. 40 
10.4.8 Exploratory Analyses ....................................................................... 40 
10.4.9 Ocular Comfort and Acceptability Analyses .................................... 40 
10.4.10 Interim Analyses ............................................................................... 40 
10.5 Additional Analyses .............................................................................................. 41 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ............................... 41 
11.1 Protection of Human Subjects ............................................................................. 41 
11.1.1 Subject Informed Consent ................................................................ 41 


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11.1.2 Institutional Review Board (IRB) Approval .................................... 41 
11.2 Ethical Conduct of the Trial ................................................................................ 41 
11.3 Subject Confidentiality ......................................................................................... 41 
11.4 Documentation ...................................................................................................... 42 
11.4.1 Retention of Documentation ............................................................. 42 
11.5 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ................................................................................................................... 42 
11.6 Monitoring and Quality Assurance ..................................................................... 43 
11.7 Handling of Biological Specimens ....................................................................... 43 
11.8 Publications ............................................................................................................ 43 
12 
REFERENCES ....................................................................................................... 44 
13 
APPENDICES ......................................................................................................... 45 
Appendix 1 
Schedule of Assessments (in recommended order) ........................... 45 
Appendix 2 
Instructions for Administration of Eye Drops .................................. 47 
Appendix 3 
Examination Procedures, Tests, Equipment, and Techniques ........ 48 
Appendix 4 
Amendment Summary of Changes .................................................... 58 
Appendix 5 
Sponsor and CRO Approvals ............................................................. 63 
Appendix 6 
Investigator’s Signature ...................................................................... 64 
 
 


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LIST OF TABLES 
 
Table 1 
Active Investigational Product ....................................................................... 22 
 
 
LIST OF FIGURES 
Figure 1 
NVU-004 Trial Flow Chart ............................................................................ 18 
 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments (in recommended order) ............................... 45 
Appendix 2 
Instructions for Administration of Eye Drops ....................................... 47 
Appendix 3 
Examination Procedures, Tests, Equipment, and Techniques ............... 48 
Appendix 4 
Amendment Summary of Changes ........................................................ 58 
Appendix 5 
Sponsor and CRO Approvals ................................................................ 63 
Appendix 6 
Investigator`s Signature ......................................................................... 64 
 
 
 


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


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


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


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Due to this mode of action subjects with DED associated with MGD were considered to 
experience the greatest benefit from the treatment. This is in line with experience from the 
Post Market Clinical Follow-up studies NT- 001, NT- 002, NT- 003 and NT- 004 with the 
perfluorohexyloctane containing medical device (NovaTears®), which showed that subjects 
with evaporative DED and MGD benefitted most. Clinical data from observational studies 
NT- 001 and NT- 002 consistently indicate that NOV03 is efficacious in treating signs and 
symptoms of mild to moderate evaporative DED and mild to moderate DED associated 
with MGD. Clinical study NT- 004 demonstrated that NOV03 increases tear film thickness 
(TFT) and lipid layer thickness (LLT) compared to saline solution and therefore provides 
further clinical evidence supportive for the use of NOV03 for evaporative forms of DED.  
For the US development of NOV03, the phase 2 clinical trial NVU-002 (SEECASE-1) was 
conducted in US clinical sites. NVU-002 was designed to specifically include a DED 
population with an MGD component. In NVU-002, subjects improved clinically 
significantly from treatment with NOV03. The magnitude of symptom improvement was 
large (in the 50% range) for many of the VAS items in the NOV03 groups. 
 
2.3 Trial Rationale 
For the US development of NOV03, a phase 2 trial NVU-002 (SEECASE-1) was 
conducted. NVU-002 was a randomized, double-masked, saline-controlled trial to evaluate 
the effect of NOV03 at two different dosing regimens (QID and BID) on signs and 
symptoms of DED after 8 weeks treatment duration.  
The trial showed efficacy of NOV03 in sign and symptom outcomes, in a highly 
symptomatic predominantly evaporative DED population with clinically significant MGD 
presence. It met its prespecified primary efficacy endpoint of superior change from baseline 
in tCFS at week 8 for both BID and QID dosing regimens compared to the combined saline 
control with high statistical significance. NOV03 showed clinically meaningful 
improvements in a variety of symptoms. The effects on Dryness Score, awareness of DED 
symptoms, and frequency of dryness were highly statistically significant over the combined 
dosing regimens of the saline control. Benefits in both signs and symptoms were dose-
schedule-dependent favoring the QID schedule over the BID schedule. The treatment 
effects started early (2 weeks) and were maintained throughout the visits. NOV03 was safe 
and well tolerated after 8 weeks of BID or QID dosing. Results are planned to be confirmed 
in the pivotal trial NVU-003 (SEECASE-2), a randomized, double-masked, saline-
controlled trial to evaluate the effect of NOV03 on signs and symptoms of Dry Eye Disease 
associated with Meibomian Gland Dysfunction. 
Subjects successfully completing NVU-003 will be offered to continue treatment in the 
phase 3, open-label extension trial NVU-004 (Kalahari OLE). NVU-004 is designed to gain 
information on long-term safety and tolerability of NOV03 QID dosing of subjects 
completing the 8-weeks treatment in trial NVU-003.  
 


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3 TRIAL OBJECTIVES 
3.1 Primary Objective 
• The primary objective of this trial is to evaluate the safety and tolerability of NOV03 
(perfluorohexyloctane) ophthalmic solution during long-term use in subjects with 
Dry Eye Disease associated with MGD. 
3.2 Secondary Objectives 
• The 
secondary 
objective 
is 
to 
evaluate 
the 
efficacy 
of 
NOV03 
(perfluorohexyloctane) solution during long-term use in subjects with Dry Eye 
Disease associated with MGD. 
 
4 TRIAL DESIGN 
4.1 Overall Trial Design 
This is a phase 3, multicenter, open-label, single-arm extension clinical trial to assess the 
extended long-term safety and tolerability of NOV03 (100% perfluorohexyloctane) at a 
QID dosing regimen. Approximately 200 subjects who completed the clinical trial NVU-
003 and meet all other NVU-004 trial eligibility criteria will be included at approximately 
20 clinical sites in the US to receive treatment with NOV03. 
 
NVU-004 eligible subjects will dose the IMP (NOV03) ophthalmologically and bilaterally 
QID for approximately 52 weeks. 
 
4.2 End of Trial Definition  
The end of the trial for an individual subject is defined as that subject’s last clinic visit.  
The end of the trial for the overall trial is defined as completion of the last visit or procedure 
as specified in schedule of assessments (Appendix 1) for all subjects in the trial. 
 
4.3 Visit Description and Telephone Calls 
Subjects will be required to sign an Informed Consent before completing any NVU-004 
trial related procedure. All trial procedures are listed in Section 8.4 and in the schedule of 
assessments Appendix 1. The ocular symptoms assessments and evaluations must be 
performed in the respective order as listed. IMP Dispensation is described in Section 7.1.4. 
 
Subjects shall be instructed not to discuss IMP characteristics and/or their experience with 
the IMP with other subjects during each visit. 
 


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Follow-up NVU-004 subject visits should not be scheduled for the same day as any NVU-
003 subject visits at a given site to prevent unblinding of NVU-003. 
 
If NVU-003 and NVU-004 subjects are present at the clinical site the same time, the site 
should take precautions to prevent subjects from interacting. 
Day 1 (Visit 1) 
The results of assessments at Visit 4 (Day 57) in study NVU-003 (=final visit) will be taken 
as Day 1 data for NVU-004. Further data/assessments to be captured will be the NVU-004 
Informed Consent, Inclusion/Exclusion Criteria to determine NVU-004 eligibility, Non-
leading Adverse Event questioning (AE query) and IMP dispensation. 
 
Subjects will be given a 4-bottle IMP supply and will self-administer a single drop of the 
trial medication into both eyes at the clinic. Each subject will be given a dosing diary to 
record the number of IMP doses taken daily. Study staff will remind the subject how to use 
the dosing diary and when the remaining doses should be taken. 
Visits 2-6 / (ET) 
Subjects will return to the clinic on week 4±2 days (Visit 2), week 12±7 days (Visit 3), 
week 26±7 days (Visit 4), week 40 ±7 days (Visit 5), week 52±7 days (Visit 6/Early 
Termination (ET)) to be evaluated for ocular and non-ocular adverse events and signs and 
symptoms of DED. IMP and the subject diary will be collected and reviewed. All used and 
unused trial medication should be returned to the clinic and a new trial medication kit will 
be dispensed.  
 
The subject will be asked to complete an eyedrop comfort and acceptability questionnaire 
during Visit 6/ET. Subjects will be discharged from the trial after all Visit 6/ET assessments 
have been completed. 
 
Telephone Calls (TC) 
Seven (7) telephone calls are scheduled at week 8±2 days (TC 1), week 16 ±7 days (TC 2), 
week 22 ±7 days (TC 3), week 30 ±7 days (TC 4), week 36 ±7 days (TC 5), week 44 ±7 
days (TC 6), week 48 ±7 days (TC 7). During each telephone call the subjects will be 
interviewed using non-leading AE questioning and asked for medical and/or concomitant 
medication updates.  
Early Termination 
Subjects who terminate early during the treatment period will be asked to complete all 
assessments as indicated at Visit 6 on the schedule of assessments prior to commencement 
of any alternative DED therapy (if considered possible). Dosing diary and trial medication 
will be collected. Subjects who are terminated early from the trial will not be replaced. 
 


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4.4 Trial Flow  
All subjects will be expected to progress from Visit 1 through trial exit at Visit 6 (week 52). 
All subjects will follow the trial structure with visits and telephone-calls (TC) as shown in 
Figure 1. Most Visit 1 assessments are the same assessments from Visit 4 in NVU-003. The 
detailed assessments are depicted in the schedule of assessment in Appendix 1. 
 
 
Figure 1 
NVU-004 Trial Flow Chart 
 
4.5 Enrollment and Treatment Assignment  
Subjects will keep the assigned unique subject number as allocated in clinical trial NVU-
003. If all inclusion and exclusion criteria are met at Visit 1, the first approximately 200 
qualifying subjects will be included in NVU-004. IRS will be used to assign drug kit 
numbers at visits 1, 3, 4 and 5.  
Each subject will spend approximately 52 weeks in the trial. The total duration of the trial 
from First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV) is expected to 
be approximately 18 months. 
 
4.6 Justification of Trial Design 
This 52-week open-label extension trial will enroll subjects successfully completing trial 
NVU-003. The open-label single-arm treatment design is deemed adequate for 
investigating long-term safety/tolerability of NOV03 QID at regular intervals in at least 100 
subjects in long term (52-week), day to day use. An interim analysis will be performed after 
100 subjects complete 26-weeks of treatment. 
4.7 Justification of Dose  
NOV03 has demonstrated efficacy for signs and symptoms of DED in the phase 2 trial 
NVU-002 at two NOV03 dosing regimens (QID and BID) versus saline. In NVU-002 the 
NOV03 QID regimen showed more pronounced effects for several efficacy parameters 


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compared to the NOV03 BID and saline regimens. Therefore, the NOV03 QID regimen 
was chosen for the phase 3 trial NVU-003 to replicate the 8-weeks efficacy and safety 
results of NVU-002. No safety and tolerability issues were observed in the 8 weeks NVU-
002 trial with this treatment schedule. Therefore, the open label extension trial NVU-004 
will use the same NOV03 dose schedule used in NVU-003. 
 
5 TRIAL POPULATION 
5.1 Number of Subjects (approximate) 
Approximately 200 subjects who completed the clinical trial NVU-003 will be enrolled at 
approximately 20 sites to achieve at least 100 subjects completing 26 weeks and 52 weeks 
dosing with respective safety and tolerability assessments. 
 
5.2 Trial population characteristics 
All subjects must be at least 18 years of age, of either gender and of any race. Subjects must 
have a reported history of dry eye in both eyes, meet all inclusion criteria and none of the 
exclusion criteria. 
 
Subjects who completed trial NVU-003 without major protocol deviations, have been 
compliant with NVU-003 trial procedures and application of IMP may be invited to enroll 
into trial NVU-004.  
 
5.3 Inclusion Criteria 
Subjects will be eligible to participate in this trial if they meet all of the following criteria:  
 
1. Have completed trial NVU-003 without major protocol deviations, and have been 
compliant with NVU-003 trial procedures and application of IMP.  
2. Have a subject reported history of DED in both eyes for at least 6 months prior to 
Visit 0 of NVU-003 and be diagnosed with DED at Visit 1 of NVU-003. 
3. Provide written informed consent.  
4. Be able and willing to follow instructions, including participation in all trial 
assessments and visits. 
 
5.4 Exclusion Criteria 
Subjects will not be eligible to participate in this trial if any of the following criteria apply: 
Subjects must not: 
1. Have permanently discontinued investigational medicinal product during NVU- 003 
for any reason. 


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2. Have any clinically significant slit-lamp findings or ocular condition at Visit 1 and/or 
in the opinion of the investigator have any findings that may interfere with trial 
parameters.  
3. Have an ocular or periocular malignancy. 
4. Have a history of herpetic keratitis. 
5. Have any planned ocular and/or lid surgeries over the trial period. 
6. Be a woman who is pregnant or planning a pregnancy. 
7. Be unwilling to submit to a urine pregnancy test at Visit 2, 3, 4, 5 and Visit 6 (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). 
8. Be a woman of childbearing potential who is not using an acceptable means of birth 
control; acceptable methods of contraception include: hormonal – oral, implantable, 
injectable, or transdermal contraceptives; mechanical – spermicide in conjunction with 
a barrier such as a diaphragm or condom; intrauterine device (IUD); or surgical 
sterilization of partner. For non-sexually active females, abstinence may be regarded as 
an adequate method of birth control; however, if the subject becomes sexually active 
during the trial, she must agree to use adequate birth control as defined above for the 
remainder of the trial. 
9. Have a known allergy and/or sensitivity to the investigational medicinal product (IMP). 
10. Be currently enrolled in an investigational drug or device trial other than NVU-003 and 
NVU-004. 
11. Have corrected visual acuity worse than or equal to logarithm of the minimum angle of 
resolution (logMAR), +0.7 as assessed by Early Treatment of Diabetic Retinopathy 
Study (ETDRS) scale in both eyes at Visit 1. 
12. Have a condition or be in a situation which the investigator feels may put the subject at 
significant risk, may confound the trial results, or may interfere significantly with the 
subject’s participation in the trial. 
 
5.5 Subject/Trial Withdrawal Criteria  
Subjects are free to discontinue their participation in the trial at any time without giving 
their reasons. 
A subject must be discontinued from the trial for any of the following reasons:  
• If at any time during the trial the investigator determines that a subject’s safety 
has been compromised; 
• Occurrence of an exclusion criterion that is clinically relevant and affects the 
subject’s safety;  
• If discontinuation is considered necessary by the investigator and/or sponsor; 
• Occurrence of 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; 


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• Withdrawal of subject`s consent. 
If a subject has failed to attend scheduled trial assessments, the investigator must determine 
the reasons and the circumstances as completely and accurately as possible. 
In case a subject has to be withdrawn from the trial, the sponsor/sponsor designee will be 
informed immediately. If there is a medical reason for withdrawal, the subject will remain 
under the supervision of the investigator until satisfactory health has returned or the 
subject´s health has reached a stable condition.  
Subjects who are withdrawn from the trial after dosing will not be replaced.  
In case of premature withdrawal from the trial, the process outlined in Section 8.4.2 should 
be followed. In any case, the appropriate electronic Case Report Form (eCRF) section 
including the reason for discontinuation as defined in Section 8.6.2 must be completed. 
The trial can be prematurely discontinued as described in Section 8.7. 
 
6 TRIAL PARAMETERS 
6.1 Primary Endpoints 
Ocular and non-ocular AEs 
 
6.2 Secondary Endpoints 
Safety Endpoints: 
 
1. Visual acuity (BCVA using ETDRS) 
2. Slit-Lamp biomicroscopy 
3. Intraocular pressure 
4. Dilated fundoscopy 
 
Other Pre-specified Efficacy Endpoints: 
1. CFB of Dryness Score (VAS) to each measured post-baseline visit. 
2. CFB in tCFS (NEI scale) to each measured post-baseline visit. 
3. CFB in CFS sub-regions (NEI scale) to each measured post-baseline visit. 
4. Proportion of tCFS responders (≥3 improvement based on NEI scale) at each measured 
post-baseline visit.  
5. Proportion of Dryness Score responders (≥30 % improvement from baseline) at each 
measured post-baseline visit. 
6. Proportion of cCFS responders (≥1 improvement based on NEI scale) at each measured 
post-baseline visit.  


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7. CFB in VAS burning/stinging, sticky feeling, foreign body sensation, itching, blurred 
vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye 
symptoms (VAS) at each measured post-baseline visit. 
8. CFB in Ocular Surface Disease Index (OSDI©) at each measured post-baseline visit. 
 
6.3 Exploratory Endpoints 
1. Meibomian Gland Assessment (MGD score) at each measured post-baseline visit. 
2. Schirmer’s Test I (without anesthesia) at each measured post-baseline visit.  
3. TFBUT at each measured post-baseline visit. 
 
6.4 Other Endpoints 
In addition to the safety and efficacy endpoints above, the comfort and acceptability of the 
trial drug will be assessed using an Eyedrop Comfort and Acceptability Questionnaire. 
 
7 TRIAL MATERIALS 
7.1 Investigational Medicinal Product 
7.1.1 IMP(s)/ Formulation 
NOV03 drug product is a thin clear, preservative-free ophthalmic solution drop (see Table 
1).  
Table 1 
Active Investigational Product 
 
Investigational Product 
Product code: 
NOV03 
Chemical name: 
Perfluorohexyloctane  
Molecular formula: 
C14H17F13 
Dosage form: 
3 mL ophthalmic solution 
Unit dose: 
11 µL drop size; 100% perfluorohexyloctane 
Route of administration: 
Topical ocular administration 
Physical description: 
Colorless and clear ophthalmic solution 
Excipients: 
None 
Manufacturer: 
Alliance Medical Products, Inc., DBA Siegfried Irvine, 
9342 Jeronimo Rd., Irvine, CA 92618, USA 
 
7.1.2 Labeling and Packaging of IMP 
IMP will be labelled according to the legal requirements and packaged into individual 
subject kits, each containing 4 bottles of NOV03. See Section 7.1.4 for details regarding 
dispensation to subjects. 


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In compliance with the Code of Federal Regulations 21 part 312, section 312.6, the labels 
for the IMP are comprised of: 
• Protocol number 
• Kit number 
• Investigational new drug statement 
• Storage conditions 
• Name and address of the sponsor 
 
7.1.3 IMP Storage 
The IMPs must be stored in a secure area accessible only to the investigator or pharmacist 
and his/her designees. IMPs must be stored at room temperature under temperature-
monitored conditions (at each clinical site) and must not be refrigerated. 
Subjects should be instructed to store IMP at room temperature and out of children’s reach 
at all times. Subjects should not use a dispensed bottle that has been opened for more than 
30 days.  
 
7.1.4 IMP Dispensation 
• At the end of Visit 1, qualified subjects will be enrolled and the investigator, or 
designee will dispense the subject one kit of IMP containing 4 individual bottles. 
• One kit will be dispensed per treatment period. The first dose of NVU-004 Study IMP 
will be administered at the clinical site. 
• At Visit 2, IMP will not be dispensed. In case the subject wants to withdraw from the 
trial during this visit, the kit should be returned. 
• At Visits 3, 4 and 5 subjects will receive a new kit of IMP.  
• At Visits 3, 4, 5 and 6 used/unused IMP will be collected from subjects for drug 
accountability. 
Subjects will be instructed to immediately contact the site if there is any problem with the 
IMP, e.g. kit/bottle(s) was damaged or lost or if the open bottle was dropped. In case the 
subject needs a replacement bottle of IMP, the next bottle from the kit can be used by the 
subject. If no bottle remains in the kit, a new kit will be assigned to the subject.  
 
7.1.5 Instructions for Use and Administration 
At Visit 1 subjects will be instructed by the site`s staff on appropriate hygiene and eye drop 
dosing technique for multiple use drops. At Visit 1, subjects will self-administer in the clinic 
NOV03 eye drops in each lower cul-de-sac of each eye under the supervision of the site 
staff as shown in Appendix 2.  
 
Subsequent eye drops are to be instilled by the subjects according to detailed written 
instructions. 


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Subjects will be instructed to instill their drops in both eyes QID for the duration of the trial. 
Clinic staff will instruct the subjects to dose at approximately the same time every day e.g. 
morning, lunch time/midday, afternoon/early evening, and at bedtime. If a dose is missed, 
then the next dose should be administered on time. 
 
Subjects will be informed on how to store (see Section 7.1.3) and dose IMP and how to 
complete their dosing diary. 
 
Dosing should be continued until the day of the next Visit (should be at least 2 hours before 
first ophthalmic examination).  
 
The IMP bottles are designed for multiple use. Subjects will be instructed to only open one 
bottle at a time. They should be instructed not to discard the empty bottles but keep them 
in the kit box and return them at their next visit in the kit box.  
 
Subjects will record in their dosing diary that their doses were taken. 
7.2 IMP Accountability 
The investigator or designated site personnel must keep an accurate accounting of IMPs 
received from the supplier by maintaining a detailed inventory. IMP shipment records will 
be verified and accountability performed by comparing the IMP shipment inventory sheet 
to the actual quantity of used/unused IMP bottles received at the site.  
 
Accurate records of receipt and disposition of the IMP (e.g. dates, quantity, subject number, 
kits used, kits unused, etc.) must be maintained by designated site personnel. This includes 
the amount dispensed to subjects, amount returned to the site by the subjects, and the 
amount returned to the sponsor or designee upon completion of the trial.  
 
Investigational trial medication orders, records of receipts, dispensing records, and 
inventory forms will be examined and reconciled by designated site personnel. At each 
visit, subjects will return all bottles to clinic staff for accountability purposes. 
Accountability will be ascertained by performing reconciliation between the amount of IMP 
cartons (kits and their components) sent to the site, the amount used and unused at the time 
of reconciliation. All investigational trial medication that is used during the course of the 
trial must be accounted for on an IMP accountability form. No IMP kits or bottles will be 
returned to the disposal facility prior to full accountability by sponsor’s monitor. 
 
7.3 IMP Handling and Disposal 
Unless otherwise directed, at the end of the trial all returned used and unused IMP must be 
directly shipped from the clinical site to the disposal facility for destruction of the 
medications. Note: The medications should not be disposed or returned prior to full 
accountability by the sponsor’s monitor.  


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The clinical site will provide a copy of all completed drug disposition forms to the sponsor 
after the completion of the trial. 
 
7.4 Other Trial Supplies 
Diaries, questionnaires, urine pregnancy tests, meibomian gland evaluator stick, Schirmer’s 
test strips, sodium fluorescein, will be provided to sites. Respective instructions are 
available in Appendix 3 and the manual of operations. 


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8 TRIAL METHODS AND PROCEDURES 
8.1 Concurrent Medications and Therapies 
The use of any concurrent medication/therapy, prescription or over-the-counter, is to be 
recorded on the subject’s source document and corresponding eCRF along with the reason 
the medication was taken. 
Therapy considered necessary for the subject’s welfare that will not interfere with the 
evaluation of the study medication may be given at the discretion of the investigator. If 
there is any question as to whether the medication may interfere, the investigator should 
contact the medical monitor or sponsor. Whenever possible, medications should be 
administered in dosages that remain constant throughout the study duration. 
Starting with Visit 2, Artificial tears (preferably preservative free) may be used, their use 
needs to be documented. The use of treatments for DED such as gels, ointments, 
TrueTearTM device (Intranasal Tear Neurostimulator), are allowed after an unsuccessful 
trial of artificial tears. 
In case clinical judgment considers it necessary, treatment with topical steroids or other 
topical prescription medications are allowed according to clinicians’ prescription. Their use 
will be documented in the subject’s source document and corresponding eCRF. 
Changes in physical ocular therapies such as lid scrubs, lid wipes, warm compresses should 
be recorded on the subject’s source document and corresponding eCRF. 
8.2 Prohibited Medications/ Treatments 
Wearing of contact lenses and ocular surgery/ocular laser treatment of any kind is not 
allowed. In case ocular surgery becomes necessary during the trial the medical monitor 
should be contacted regarding further NOV03 treatment continuation. LipiFlow procedure 
or any kind of other procedures affecting meibomian glands during the trial is not allowed.  
Concurrent enrollment in another investigational drug or medical device trial is not 
permitted. 
 
8.3 Restrictions and Prohibitions 
Subjects will be asked to refrain from the following, for 24 hours prior to their visits: 
• Dangerous sport activities (e.g. skiing, mountain climbing, etc.). 
• Challenging climates (e.g. smoking rooms, sauna, airplane etc.). 
Subjects will be asked to refrain from the following for 12 hours prior to their visits: 
• Swimming in a chlorinated pool. 
In case visual disturbances should occur upon instillation of the drop the subject is 
advised not to drive or use machinery until such effects have disappeared. 


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8.4 Examination Procedures 
8.4.1 Procedures to be performed at each trial visit with regard to trial objective(s) 
See Appendix 1 for a schedule of visits and measurements in recommended order. 
Appendix 3 describes the eye examinations. These should not be done earlier than 2 hours 
after IMP instillation. Subjects shall bring their trial medication to each visit. 
Visit 1 (Day 1) 
Note: Assessments from NVU-003 are depicted in italics. 
• Informed consent / HIPAA 
• At the beginning of the visit the subject will be asked about the time of last dose. 
Assessments should be performed at least 2 hours after last dose of IMP; 
• Medical/Surgical History (see Section 9.1 on how to record medical history and 
ongoing AEs);  
• Demographics (from V0 in NVU-003); 
• Previous/Concomitant Medication (from V4 in NVU-003); 
• Review of inclusion / exclusion criteria; 
• Urine Pregnancy test (from V4 in NVU-003); 
• Dryness Score (VAS Severity of Dryness) (from V4 in NVU-003); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, itching, blurred 
vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye 
symptoms (from V4 in NVU-003); 
• Ocular Surface Disease Index (OSDI©) questionnaire (from V4 in NVU-003); 
• Visual acuity (ETDRS) (from V4 in NVU-003); 
• Slit-Lamp biomicroscopy (from V4 in NVU-003); 
• Tear Film Break-up Time (TFBUT) (from V4 in NVU-003); 
• Fluorescein staining (NEI scale) (from V4 in NVU-003); 
• Meibomian gland assessment (MGD score) (from V4 in NVU-003) (wait 5 min 
before start of Schirmer`s Test); 
• Schirmer’s Test I (without anesthesia) (from V4 in NVU-003); 
• Intraocular Pressure (from V4 in NVU-003); 
• Dilated Fundoscopy (from V4 in NVU-003); 
• Non-leading AE questioning (Adverse event query); 
• In-office dose of IMP; 
• Dispensation of dosing diary and IMP for self-administered dosing until Visit 3; 
o Subjects will be instructed how to administer IMP; 
o Subjects will be instructed to dose with IMP on the morning of their next 
visit at least 2 hours before the start of their visit (Visit 2); 
o Subjects will be instructed on how to fill the dosing diary. 
• Dispensation of one IMP kit; 
• Subjects are scheduled for Visit 2 
 
 
 


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Visit 2 (week 4 ± 2 days), Visit 3 (week 12 ± 7 days), Visit 4 (week 26 ± 7 days), Visit 5 
(week 40 ± 7 days):  
• At the beginning of the visit the subject will be asked about the time of 
last dose. Assessments should be performed at least 2 hours after last 
dose of IMP; 
• Collection and review of IMP and dosing diary; 
o Calculate subject compliance with doses in the subject diary as 
described in Section 8.5 
o Ask subject if he/she dosed with IMP the morning of Visit 2 and, if 
applicable, record the time of the dose 
• Concomitant Medication update; 
• Urine Pregnancy Test (as needed) 
• Dryness Score (VAS Severity of Dryness); 
• VAS for burning/stinging, sticky feeling, foreign body sensation, 
itching, blurred vision, sensitivity to light, pain, frequency of dryness, 
and awareness of dry eye symptoms; 
• Ocular Surface Disease Index (OSDI©) questionnaire;  
• Visual acuity (ETDRS); 
• Slit-Lamp biomicroscopy; 
• Tear Film Break-up Time (TFBUT);  
• Fluorescein staining (NEI scale); 
• Meibomian gland assessment (MGD score) (wait 5 min before start of 
Schirmer`s Test); 
• Schirmer’s Test I (without anesthesia) (at Visit 4); 
• Intraocular Pressure; 
• Dilated Fundoscopy (at Visits 3, 4, 5); 
• Non-leading AE questioning (Adverse event query); 
• Dispensation of dosing diary; 
o Subjects will be instructed how to administer IMP; 
o Subjects will be instructed to dose with IMP on the morning of their 
next visit at least 2 hours before the start of their visit ; 
o Subjects will be instructed on how to fill the dosing diary. 
• Drug Dispensation of one kit (at Visits 3, 4, 5); 
• Subjects are scheduled for the next Visit 
 
 
Visit 6 (week 52± 7 days) or ET: 
• At the beginning of the visit the subject will be asked about the time of 
last dose. Assessments should be performed at least 2 hours after last 
dose of IMP; 
• Collection and review of IMP and dosing diary; 
• Concomitant Medication update; 
• Urine Pregnancy test; 
• Dryness Score (VAS Severity of Dryness); 


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• VAS for burning/stinging, sticky feeling, foreign body sensation, 
itching, blurred vision, sensitivity to light, pain, frequency of dryness, 
and awareness of dry eye symptoms; 
• Ocular Surface Disease Index (OSDI©) questionnaire; 
• Eyedrop Comfort and Acceptability Questionnaire; 
• Visual acuity (ETDRS); 
• Slit-Lamp biomicroscopy; 
• Tear Film Break-up Time (TFBUT); 
• Fluorescein staining (NEI scale); 
• Meibomian gland assessment (MGD score) (wait 5 min before start of 
Schirmer`s Test);   
• Schirmer’s Test I (without anesthesia); 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Non-leading AE questioning (Adverse event query); 
• Trial Exit. 
 
TC 1-7 (Weeks 8/ 16/ 22/ 30/ 36/ 44/ 48 ± 7 days) 
• Medical/Concomitant Medication Update 
• Recording of Adverse Events (see also Section 9.1) 
 
8.4.2 Early Termination/Discontinuation 
Data from subjects discontinuing after randomization will be captured completely in the 
eCRF including Early Termination Visit and reason for discontinuation. If a dosed subject 
is discontinued from the trial prior to Visit 6 (week 52), then all evaluations planned for 
Visit 6 (week 52) should be performed on the day of discontinuation (early termination 
visit) or at the discretion of the investigator.  
 
8.4.3 Unscheduled Visits 
An unscheduled visit may be performed during the course of the trial 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 unscheduled visit 
procedure listed in the eCRF that is not performed should be indicated as “not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
• Slit-Lamp biomicroscopy; 
• Visual acuity; 
• Intraocular pressure; 
• Dilated fundoscopy; 
• Urine pregnancy test (for women of childbearing potential); 
• Assessment of AEs; 
• Assessment of concomitant medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 


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8.5 Compliance with Protocol 
Subjects will be instructed on proper instillation and storage of IMP at Visits 1, 2, 3, 4 and 
5 and provided with written instructions (Appendix 2). Subject diaries and IMP (used and 
unused bottles) will be collected from subjects at each visit from Visit 2 up to and including 
Visit 6 to assess subject dosing compliance.  
 
Subject dosing compliance will be determined by the subject’s response or lack thereof to 
the prompt “Was the dose taken?” in the subject diary. If more than 20% of the responses 
to the total expected dose-taken prompts are checked “no,” left blank, or missing, then the 
subject will be deemed noncompliant for dosing and a deviation recorded. 
 
8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the trial. 
 
8.6.2 Discontinued subjects 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to the CRO and/or trial sponsor and will be clearly documented in the eCRF as: 
• Adverse event; 
• Lack of efficacy; 
• Withdrawal by subject; 
• Protocol violation; 
• Lost to follow up; 
• Sponsor termination of trial; 
• Death 
• Other 
 
Subjects must be discontinued as outlined in Section 5.5. 
Subjects who discontinue for any reason after randomization will not be replaced. 
 
8.7 Trial Termination 
The whole trial may be discontinued prematurely in the event of any of the following:  
 
• New information leading to unfavorable risk-benefit judgment of the IMP, e.g. due to: 
o Occurrence of significant previously unknown adverse reactions or 
unexpectedly high intensity or incidence of known adverse reactions, or 
o Other unfavorable safety findings. 


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• Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical 
reasons. 
• Poor enrollment of subjects making completion of the trial within an acceptable time 
frame unlikely. 
• Discontinuation of development of the sponsor’s IMP. 
• Terminated or suspended upon request of Health Authorities. 
 
Health Authorities and Institutional Review Boards (IRBs)/ Independent Ethics 
Committees (IECs) will be informed about the discontinuation of the trial in accordance 
with applicable regulations. 
 
8.8 Trial Duration 
An individual subject’s participation will involve 6 visits over approximately a 52-week 
period. After the trial, subjects will be treated according to standard of care, at the discretion 
of the treating physician. The total duration of the trial from FSFV until LSLV is expected 
to be 18 months. 
 


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9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related. An AE can 
therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), 
symptom, or disease occurring after the subject signature of the ICF without any judgment 
on causality. 
 
AEs ongoing at the time of Visit 4 (Day 57) in trial NVU-003 and prior to IMP 
administration at Visit 1 of NVU-004 will not be considered an AE for NVU-004. These 
will be recorded as medical history in NVU-004. If there is a worsening of such medical 
history after administration of the IMP, this should be considered a new AE and reported.  
 
Worsening of DED will be considered an AE only if the dry eye status of the subject 
exceeds their previous experiences with the condition. This will be determined by the 
subject and the investigator. 
 
A clinically significant visual acuity worsening in NVU-004 (defined as an increase of 0.22 
or greater in logMAR score) from Visit 0 in NVU-003 will be considered an Adverse Event. 
 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IMP, expectedness, action(s) taken, seriousness, and outcome of 
any sign or symptom observed by the physician or reported by the subject upon non-leading 
AE questioning. 
 
AEs (both elicited and observed) will be monitored throughout the trial. The investigator 
will promptly review all AEs for accuracy and completeness. All AEs will be documented 
on the appropriate source document and eCRF. 
 
 
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE 
as determined by the investigator or reported to him/her by the subject. The assessment of 
severity is made irrespective of relationship to IMP or seriousness of the event and should 
be evaluated according to the following scale: 
• Mild: Event is noticeable to the subject but is easily tolerated and does not 
interfere with the subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
 


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


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• Recovered/Resolved with Sequelae 
• Lost to Follow-up 
• Fatal 
• Unknown 
 
9.2 Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator, medical monitor or 
sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
o Note: An AE is considered “life-threatening” if, in the view of either the 
investigator, medical monitor or sponsor, its occurrence places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in 
a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
o Note:  The term “inpatient hospitalization” refers to any inpatient 
admission (even if less than 24 hours). For chronic or long-term inpatients, 
inpatient admission includes transfer within the hospital to an 
acute/intensive care inpatient unit. Inpatient hospitalization does not 
include: 
emergency 
room 
visits; 
outpatient/same-day/ambulatory 
procedures; observation/short stay units; rehabilitation facilities; hospice 
facilities; nursing homes; or clinical research/phase 1 units. 
o Note:  The term “prolongation of existing hospitalization” refers to any 
extension of an inpatient hospitalization beyond the stay anticipated or 
required for the reason for the initial admission as determined by the 
investigator or treating physician; 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
o Note: A serious adverse event (SAE) specifically related to visual threat 
would be interpreted as any potential impairment or damage to the subject’s 
eyes (e.g. hemorrhage, retinal detachment, central corneal ulcer or damage 
to the optic nerve). 
• A congenital anomaly/birth defect; 
• Medically important 
o Important Medical Events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 


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9.3 Procedures for Reporting Adverse Events and Serious Adverse 
Events 
All AEs and their outcomes must be reported to CRO, the trial sponsor, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate source document and eCRF page. 
 
9.3.1 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IMP, must be 
immediately (i.e. within a maximum 24 HOURS after becoming aware of the event) 
reported to CRO Drug Safety Navigator (who will notify the medical monitor and the trial 
sponsor). All information relevant to the SAE must be recorded on the appropriate SAE 
report form. The CRO Drug Safety Navigator 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 CRO Drug Safety Navigator. If the investigator is not able to successfully 
fax the SAE Report or verify it was successfully received by CRO Drug Safety Navigator, 
the investigator must call the CRO SAE Hot Line to report the SAE and follow-up with the 
CRO Drug Safety Navigator Associate by phone (see phone/fax numbers and email in 
safety management plan (SMP)). 
 
 
The information entered must contain sufficient information to enable medical assessment 
by the medical monitor. At a minimum, the initial SAE report should contain the following 
information: 
 
● Subject’s trial ID number 
● Description of the Serious Adverse Event 
● Date of the Serious Adverse Event  
● Criterion for seriousness 
● Preliminary assignment of causality to IMP 
 
All information relevant to the SAE must be recorded on the appropriate case report forms. 
The investigator is obligated to pursue and obtain information requested by CRO Drug 
Safety Navigator, CRO and/or the sponsor in addition to that information reported on the 
case report form. All subjects experiencing a SAE must be followed up and the outcome 
reported. 
The investigator must obtain and maintain in his/her files all pertinent medical records, 
information, and medical judgments from colleagues who assisted in the treatment and 
follow-up of the subject; provide CRO Drug Safety Navigator and the trial sponsor with a 
complete case history, which includes a statement as to whether the event was or was not 
suspected to be related to the use of the IMP; and inform the IRB of the AE within their 
guidelines for reporting SAEs. 


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All SAEs will be reported as of the signature of Informed Consent. All SAEs will be 
followed until resolution, stabilization, the event is otherwise, explained, or the subject is 
lost to follow-up. 
 
9.3.2 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 CRO Drug Safety Navigator within 24 hours after the 
site becomes aware of the event, via the SAE reporting process outlined above. All 
SAE/SUSARs will be promptly reported to the IRB/IEC and governing health authorities 
(e.g. United States Food and Drug Administration [FDA]) as required by the IRB/IEC, 
federal, state, and local regulations and timelines. 
 
9.4 Procedures for Unmasking of IMP 
All subjects, investigators, and trial personnel involved with the conduct of the trial will 
be unmasked as this is a single-arm and open label extension trial. 
 
9.5 Type and Duration of the Follow-up of Subjects after Adverse 
Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to follow-
up or until the AE is otherwise classified. Resolution means the subject has returned to 
baseline state of health or the investigator does not expect any further improvement or 
worsening of the AE. If the subject is lost to follow-up, the investigator should make 3 
reasonable attempts to contact the subject via telephone, post, or certified mail. All follow-
up will be documented in the subject’s source document. Non-serious AEs identified on the 
last scheduled contact must be recorded on the AE eCRF with the status noted.  
 
If the investigator becomes aware of any new information regarding an existing SAE (i.e. 
resolution, change in condition, or new treatment), a new SAE Report Form must be 
completed and faxed to CRO Drug Safety Navigator within 24 hours of the site’s awareness 
of the new information. The original SAE form is not to be altered, but a new SAE Report 
Form must be completed and identified consecutively based on the previous report form 
(i.e. Initial Report, Follow-up #1, Follow-up #2, etc.). The report must describe whether the 
event has resolved or continues and how the event was treated. 
9.6 Reporting Pregnancies 
Pregnancy itself is not considered an AE or SAE (unless there is a suspicion that the IMP 
may have interfered with the effectiveness of a contraceptive medication). Pregnancy is an 
important medical event that must be followed up. Any pregnancy that occurs during the 
clinical trial where the fetus could have been exposed to IMP must be followed through the 
outcome of the pregnancy.  


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It is the responsibility of the Investigator to obtain the outcome and condition of the infant 
information within 30 calendar days after the initial notification and approximately 30 
calendar days postpartum. 
 
If a subject or investigator suspects that the subject may be pregnant prior to IMP 
administration, the IMP must be withheld until the results of pregnancy testing are 
available. If pregnancy is confirmed, the subject must not receive IMP and must not be 
enrolled in the trial. If pregnancy is suspected while the subject is receiving IMP treatment, 
the IMP must immediately be withheld until the result of pregnancy testing is known. 
If a female reports a pregnancy or has a positive pregnancy test during the trial, then the 
subject should be discontinued from the study and the investigator must report the 
pregnancy and the outcome of the pregnancy to the CRO Drug Safety Navigator Associate 
within 24 hours of learning about the pregnancy. 
A Pregnancy Reporting Form will be completed by the trial site’s principal investigator and 
sent to CRO Drug Safety Navigator (see SMP). The CRO Drug Safety Navigator will 
forward the documentation to the medical monitor and the sponsor for review. 
At the completion of the pregnancy, the Pregnancy Outcome Form is to be submitted to the 
CRO Drug Safety Navigator via the SAE contact details. The CRO Drug Safety Navigator 
will manage the query and reconciliation process until the pregnancy documentation is 
complete. 
 


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10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
The following analysis populations will be considered: 
 
Safety Set (SAF) – The SAF includes all enrolled subjects who have received at least one 
dose of the investigational product in this study. The SAF will be analyzed for all 
assessments. Subjects in the SAF will be analyzed as treated.  
 
The statistical analysis of baseline, and primary/secondary endpoint data will be performed 
for the SAF.  
 
Data will be summarized by treatment group as received in NVU-003 and overall. Group 1 
and group 2 consist of subsets of subjects who received masked treatment with NOV03 or 
saline, respectively, in NVU-003. 
 
10.2 Statistical Hypotheses 
There are no formal hypotheses to be tested in this open-label safety extension trial. 
 
10.3  Sample Size 
Approximately 200 subjects will be enrolled in order to ensure that at least 100 evaluable 
subjects complete the week 26 treatment period and at least 100 evaluable subjects complete 
the week 52 treatment period. 
 
With 100 subjects completing the week 52 (or week 26) treatment period, the study will 
have 95% or greater chance of observing adverse events that occur at a true incident rate of 
3.0% or higher.  
 
10.4 Statistical Analysis 
10.4.1 General Considerations 
Quantitative variables will be summarized using number of subjects (n), mean, median, 
standard deviation, minimum and maximum. Qualitative variables will be summarized 
using counts and percentages.  
 
Summaries will be provided for demographics, 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. 


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Presentation will be by treatment group for subjects treated with NOV03 in NVU-003 and 
subjects treated with the saline comparator in NVU-003 as well as overall. 
The results of assessments performed at multiple visits will be presented by visit as 
appropriate unless otherwise specified. 
The results of bilateral ocular assessments will be summarized separately for study and 
fellow eyes. 
Baseline measures are defined as the measure prior to the administration of IMP in the 
double masked trial NVU-003, e.g. baseline in NVU-003 and NVU-004 are identical. CFB 
will be calculated as Value at Follow-up Visit – Value at Baseline Visit.  
 
10.4.2 Unit of Analysis 
For efficacy endpoints, the unit of analysis will be the study eye which was determined 
during NVU-003. This information will be transferred to this NVU-004 trial. 
 
10.4.3 Missing Data 
The primary analysis will be completed on the SAF with available data per subject.  
 
10.4.4 Multiplicity Considerations 
This section is not applicable. 
 
10.4.5 Primary Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Dosing information will be summarized overall and by treatment from NVU-003 and listed 
for each subject. Discontinuation of treatment will be summarized. The primary reason for 
IMP discontinuation will also be summarized by treatment group as received in NVU-003. 
Adverse events (AEs) will be coded using the MedDRA dictionary. An AE will be defined 
as treatment emergent if it occurs or worsens after the first dose of trial treatment in clinical 
trial NVU-004.  
Frequencies and percentages of subjects with TEAEs, treatment related TEAEs, serious 
TEAEs, and TEAEs causing premature discontinuation will be provided.  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 
provided for ocular and non-ocular AEs.  Ocular AEs will be summarized at the subject 
level, at the eye level, and separately for study and fellow eyes.  
 
The treatment groups as assigned in NVU-003 will be compared descriptively with regard 
to safety endpoints. No inferential comparison will be conducted. 


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Concomitant medications will be coded using the most recent version of WHO-Drug 
Dictionary. 
 
10.4.6 Secondary Safety Analyses 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, dilated 
fundoscopy, and intraocular pressure will be summarized by visit and by treatment group 
as received in NVU-003 using descriptive statistics. Changes from baseline (baseline as 
defined in clinical trial NVU-003) will also be summarized where appropriate. For 
assessments performed by eye, study eye and fellow eye will be summarized separately.  
 
10.4.7 Other Pre-specified Efficacy Analyses 
The analysis of other pre-specified efficacy endpoints will use the SAF with available data 
per subject.  
 
Quantitative other pre-specified efficacy endpoints will be summarized descriptively (n, 
mean, standard deviation, median, min, and max) by visit and by treatment group as 
assigned in NVU-003.  
 
Dichotomous other pre-specified efficacy endpoints will be summarized descriptively 
(frequency and percentage). 
 
10.4.8 Exploratory Analyses 
Exploratory endpoints MGD score, Schirmer`s Test I, and TFBUT will be summarized 
descriptively. 
 
10.4.9 Ocular Comfort and Acceptability Analyses 
Eyedrop comfort and acceptability will be assessed on the SAF population with available 
data per subject. The data will be summarized descriptively. 
 
10.4.10 Interim Analyses 
An interim safety analysis is planned for the first 100 subjects completing 26 weeks 
treatment with IMP including all assessments of Visit 4. This 26-week interim report will 
be used to submit the initial NDA. The safety analyses will be identical to the final analyses 
after 52 weeks of treatment with IMP including Visit 6 (52 weeks). 
 


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10.5 Additional Analyses 
Additional analysis of study measures, combining / pooling data with trial NVU-003 and / 
or NVU-002 might be described in a statistical analysis plan, separate from the formal study 
statistical analysis plans.  
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This trial will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs), including the International Conference on Harmonization (ICH) Guidelines, and 
in general, consistent with the Declaration of Helsinki. In addition, all applicable local, 
state, and federal requirements relevant to the use of IMPs in the countries involved will be 
adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any trial specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject prior to 
enrollment into the trial. 
 
All informed consent/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 (e.g. due 
to a protocol amendment or significant new safety information), it is the investigator’s 
responsibility to ensure that the amended informed consent is reviewed and approved by 
the governing IRB/IEC and that it is read, signed and dated by all subjects subsequently 
enrolled in the trial as well as those currently enrolled in the trial. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This trial is to be conducted in accordance with Institutional Review Board regulations 
(U.S. 21 CFR Part 56.103). Only an IRB/IEC approved version of the informed consent 
form will be used. 
 
11.2 Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that originated with 
the Declaration of Helsinki. 
 
11.3 Subject Confidentiality 
All personal trial subject data collected and processed for the purposes of this trial should 
be maintained by the investigator and his/her staff with adequate precautions as to ensure 


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that the confidentiality of the data is in accordance with local, state, and federal laws and 
regulations. 
 
Monitors, auditors and other authorized representatives of CRO Drug Safety Navigator, the 
sponsor, the IRB/IEC approving this trial, the FDA, the Department of Health and Human 
Services, other domestic government agencies, and other foreign regulatory agencies will 
be granted direct access to the trial subject’s original medical and trial records for 
verification of the data and/or clinical trial procedures. Access to this information will be 
permitted to the aforementioned individuals to the extent permitted by law. 
 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the IMP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s trial subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and EKGs. The investigator’s electronic copy of the eCRFs serves as the 
investigator’s record of a subject’s trial-related data. 
 
11.4.1 Retention of Documentation 
All trial related correspondence, subject records, consent forms, record of the distribution 
and use of all IMP and copies of case report forms should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region; or until at least 
two years have elapsed since the formal discontinuation of clinical development of the IMP. 
These documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be 
retained. The investigator must notify the sponsor prior to destroying trial documentation 
even after the above-mentioned time has passed. 
 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping trial records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
 
11.5 Recording of Data on Source Documents and Electronic Case 
Reports Forms (eCRFs) 
All subject data will be captured in the subject source documents which will be transcribed 
to the eCRFs. The investigator is responsible for ensuring that trial data is completely and 
accurately recorded on each subject’s eCRF, source documents, and all trial-related 


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materials. All trial data should also be attributable, legible, contemporaneous, and original. 
Recorded data should only be corrected in a manner that does not obliterate, destroy, or 
render illegible the previous entry (e.g. by drawing a single line through the incorrect entry 
and writing the revision next to the corrected data). 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 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. An audit trail will be maintained within the electronic system to 
capture all changes made within the eCRF database. After the end of the trial 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. 
 
11.6 Monitoring and Quality Assurance 
During the course of the trial a clinical research associate (CRA) will make routine site 
visits to review protocol compliance, assess IMP accountability, and ensure the trial is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the trial monitoring (including medical monitoring) will 
be outlined in a monitoring plan. 
Domestic and foreign regulatory authorities, CRO Drug Safety Navigator and quality 
assurance, sponsor and or its designees may carry out on-site inspections and/or audits 
which may include source data checks. Therefore, direct access to the original source data 
will be required for inspections and/or audits. All inspections and audits will be carried out 
with consideration to data protection as well as subject confidentiality to the extent that 
local, state, and federal laws apply. 
 
11.7 Handling of Biological Specimens 
Not applicable. 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved 
in the trial. Authorship will be established before writing the manuscript. The trial sponsor 
will have the final decision regarding authorship, manuscript and publication. 
 
 
 


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12 REFERENCES 
1. Benitez-del-Castillo J, Labetoulle M, Baudouin C, et al. (2017). Visual acuity and 
quality of life in DED: Proceedings of the OCEAN group meeting. The Ocular Surface 
15, 169-178. 
2. Craig, J. P. (2017). TFOS DEWS II Definition and Classofocation Report. The Ocular 
Surface, 15, 276-283. 
3. Le Q, Zhou X, Ge L, Wu L, Hong J, Xu J. (2012). Impact of dry eye syndrome on 
vision-related quality of life in a non-clinic-based general population. BMC 
Ophthalmology ; 12(22): 1-8. 
4. Lemp M. (1995). Report of the National Eye Institute/Industry Workshop on Clinical 
Trials in Dry Eyes. CLAO J.; 21 (4): 221-32. 
5. Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. (2003). Prevalence of dry eye 
among an elderly Chinese population in Taiwan: the Shihpai Eye Trial. Ophthalmology 
; 110(6):1096-101. 
6. McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. (1998) The 
epidemiology of dry eye in Melbourne, Australia. Ophthalmology ; 105(6):1114-9. 
7. Schaumberg DA, Sullivan DA, Dana MR. (2002). Epidemiology of dry eye syndrome. 
Adv Exp Med Biol, 506, 989-98. 
8. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. (2003). Prevalence of dry eye 
syndrome among US women. Am J Ophthalmol, 136, 318-26. 
9. Schaumberg DA, Dana R, Buring JE, Sullivan DA (2009). Prevalence of dry eye disease 
among US men: estimates from the Physician's Health Studies. Arch Ophthalmol, 127, 
763-8. 
10. Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W. (2003). Utility 
Assessment among patients with dry eye disease. Ophthalmology; 110: 1412-1419. 
 


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13 APPENDICES 
Appendix 1 Schedule of Assessments (in recommended order) 
Procedure 
Visit 1 
(Day1)
2  
Visit 2 
(week 4 ± 
2 days) 
TC 1 
(week 8 ± 
2 days) 
Visit 3 
(week 12 ± 
7 days) 
TC 2 
(week 16 ± 
7 days) 
TC 3 
(week 22 ± 
7 days) 
Visit 4 
(week 26 ± 
7 days) 
TC4 
(week 30 ± 
7 days) 
TC5 
(week 36 ± 
7 days) 
Visit 5 
(week 40± 
7 days 
TC 6 
(week 44 ± 7 
days) 
TC 7 
(week 48 ± 
7 days) 
Visit 6/ET 
(week 52 ± 7 days) 
Informed Consent / HIPAA 
X
4 
  
  
  
  
  
  
  
  
  
  
  
  
Medical / Surgical History and Demographics 
X
3 
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant Medication 
X
3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X
4 
  
  
  
  
  
  
  
  
  
  
  
  
Urine Pregnancy Test (as needed)
1 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Dryness Score (VAS severity of dryness) 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
VAS  
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
OSDI 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Eyedrop Comfort and Acceptability 
Questionnaire 
  
  
  
  
  
  
  
  
  
  
  
  
X 
Visual Acuity (ETDRS) 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Slit-Lamp Biomicroscopy 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
TFBUT 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Corneal Fluorescein Staining (NEI scale) 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Meibomian Gland Assessment (MGD score) 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Schirmer’s Test I (without anesthesia) 
X
3 
  
  
  
  
  
X 
  
  
  
  
  
X 
Intraocular Pressure 
X
3 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Dilated Fundoscopy 
X
3 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Adverse Event Query 
X
4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
In-office instillation trial medication 
X
4 
  
  
  
  
  
  
  
  
  
  
  
  
Dosing Diary Dispensation/Review/Collection 
X
4 
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
Dispensation of trial medication 
X
4 
  
  
X 
  
  
X 
  
  
X 
  
  
  
Collection of trial medication 
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Trial Exit 
  
  
  
  
  
  
  
  
  
  
  
  
X 


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1 For women of childbearing potential 
2 For subjects continuing from NVU-003 to NVU-004, V1 of NVU-004 will be performed at V4 (Day 57) of NVU-003.  
3 Assessment Results being transferred from NVU-003 V4 (Day 57) to NVU-004 V1 (Day 1) 
4 Assessments to be performed for NVU-004 
 
ETDRS = Early Treatment of Diabetic Retinopathy Study; HIPAA = Health Information Portability and Accountability Act; NEI = National Eye Institute; OSDI = 
Ocular Surface Disease Index; TFBUT = Tear Film Break Up Time; ET= Early Termination; VAS: burning/stinging, sticky feeling, foreign body sensation, itching, 
blurred vision, sensitivity to light, pain, frequency of dryness, and awareness of dry eye symptoms  
 
 


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Appendix 2 Instructions for Administration of Eye Drops 
Instructions for Use 
Subjects will be instructed to instill one drop in each eye four times daily and as 
illustrated below. Subjects will be instructed to use a second drop only if the first drop 
misses the eye. Subjects will be given detailed instructions on study drug administration 
(see below), accountability, and storage. 
Proper Handling of Eye drop Container 
Figure A. Opening the bottle 
1. Unscrew the cap of the bottle. 
2. Prior to the first administration of the study drug you must separate the cap from the 
safety seal ring below the cap and remove the safety seal ring. 
3. Do not touch the dropper after removing the cap. 
4. To avoid loss of solution please read steps 5 to 7 carefully before applying the eye 
drops. 
5. Hold the opened bottle with the dropper pointing upwards and gently press the bottle 
between thumb and index finger. 
6. Keep the bottle under slight pressure and turn the bottle until the dropper points 
downwards. 
7. With the dropper pointing downwards reduce the pressure on the bottle to allow some 
air to flow into the bottle. 
Figure B. Instilling the drop 
1. Lean your head back slightly and carefully pull down your lower eyelid. Look upwards. 
2. Hold the opened bottle with the dropper pointing downwards above your eye. Apply 
gentle pressure on the bottle and administer 1 drop per eye. Note: Due to the special 
properties of the study drug you may not feel the drop falling into your eye. In this case 
we recommend application in front of a mirror. 
3. Do not touch the dropper with your eye or lashes. 
4. For an even distribution, close your eyes after applying the study drug. 
5. Put the screw cap back on after administration. 
If a subject has difficulties with step 4 to 7 of Figure A, advise to refer to step 2 of Figure 
B: subject to squeeze bottle very gently or to wait until drop drips from the bottle without 
squeezing. 
 
A) 
B) 
A) 
B) 
A) 
B) 
A) 
B) 


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Appendix 3 Examination Procedures, Tests, Equipment, and Techniques 
The following examination procedures, tests, equipment and techniques are listed in this 
Appendix: 
 
• Dryness Score (VAS Severity of Dryness) 
• Visual Analog Scale (VAS) 
• Ocular Surface and Disease Index (ODSI©) questionnaire 
• Visual Acuity 
• Slit-Lamp Biomicroscopy 
• Tear Film Break-up Time (TFBUT) 
• Fluorescein Staining (NEI/Industry workshop Scale) 
• Meibomian Gland Assessment (MGD score) 
• Schirmer’s Test I (without anesthesia) 
• Procedure for Evaluating Intraocular Pressure 
• Procedure for Conducting Dilated Fundoscopy 
• Eyedrop Comfort and Acceptability Questionnaire  
• Dosing Diary 
 
Dryness Score 
Study staff will ask subjects to rate their severity of ocular dryness (both eyes 
simultaneously) by placing a vertical mark on the horizontal line to indicate the level of 
discomfort (0 corresponds to “no dryness” and 100% corresponds to “maximal dryness”). 
The assessment line length of the scale will be 100 mm (10 cm) and will be according to 
the following depiction: 
 
Please rate this symptom by placing a vertical mark on the horizontal line to indicate the level of 
discomfort associated with dryness. 0% corresponds to “no discomfort” and 100% corresponds to 
“maximal discomfort”. 
 
 
 


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Visual Analog Scale (VAS) 
Study staff will ask subjects to rate their ocular symptoms (both eyes simultaneously) due 
to ocular dryness by placing a vertical mark on the horizontal line to indicate the level of 
discomfort (0 corresponds to “no dryness” and 100% corresponds to “maximal dryness”). 
Subjects will be asked about the severity of dry eye symptoms: sticky feeling, burning / 
stinging, foreign body sensation, itching, blurred vision, sensitivity to light, and pain. 
Subjects will also be asked about their awareness of their dry eye symptoms and frequency 
of dryness. The assessment line length of the scale will be 100 mm (10 cm) and will be 
according to the following depiction: 
 
  


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Ocular Surface and Disease Index (OSDI)© questionnaire 
 


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Visual Acuity Procedures 
LogMAR Visual Acuity (VA) must be assessed using an ETDRS-like chart. The procedure 
used will be consistent with the recommendations provided for using the ETDRS eye charts. 
Visual Acuity should be evaluated at the beginning of each visit in the study (i.e. prior to 
slit-lamp examination). Subjects should use the most recent correction to attain their best-
corrected visual acuity (BCVA) during all VA assessments. Pinhole testing is not permitted. 
Equipment 
The visual acuity chart to be used is the ETDRS chart. In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only ETDRS Series 
2000 Chart 1 & 2, and the right eye (OD) should be tested first. For reflectance (wall) charts, 


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the chart should be placed frontally and well illuminated. The subject viewing distance 
should be exactly 4 meters (13 feet). 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The subject should attempt to read each letter, line-by-line, left to right, beginning with line 
1 at the top of the chart. The subject should be told that the chart has letters only, no 
numbers. If the subject reads a number, he/she should be reminded that the chart contains 
no numbers, and the examiner should then request a letter in lieu of the number. The subject 
should be asked to read slowly, so as to achieve the best identification of each letter. He/she 
is not to proceed to the next letter until he/she has given a definite response. 
If the subject changes a response (e.g. 'that was a "C" not an "O"') before he/she has read 
aloud the next letter, then the change must be accepted. If the subject changes a response 
having read the next letter, then the change is not accepted. The examiner should never 
point to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject 
says he/she cannot read a letter, he/she should be encouraged to guess. If the subject 
identifies a letter as one of two letters, he/she should be asked to choose one letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read incorrectly 
should be noted. 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number of 
letters missed up to and including in the last line read. This total sum represents the logMAR 
visual acuity for that eye. 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 
0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 
0.2 and on line 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
 
Repeat the procedure for the left eye (OS). 
In order to provide standardized and well-controlled assessments of visual acuity during the 
study, all visual acuity assessments at a single site must be consistently done using the same 
lighting conditions and same correction if possible during the entire study. If the same 
correction cannot be used (i.e. a subject forgets his/her glasses), the reason for the change 
in correction should be documented. 
Note: A clinically significant visual acuity decrease (defined as an increase of 0.22 or 
greater in logMAR score) from Visit 0 (NVU-003) will be considered an Adverse Event. 


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Slit-Lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed during the study. Observations will be graded 
as Normal or Abnormal. Abnormal findings, which are clinically significant, will be 
described. The following will be examined at each visit: 
• Lids 
• Cornea  
• Conjunctiva  
• Anterior Chamber 
• Iris 
• Lens 
 
External magnification and biomicroscopy will be performed using a slit-lamp.  
Magnification will be consistent with standard clinical practice. The subject will be seated 
for the assessment. 
 
Tear Film Break-Up Time (TFBUT) 
The examiner will instill 5 µL of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. To thoroughly mix the fluorescein with the tear 
film, the subject will be instructed to blink several times. The examiner should wait 
approximately 30 seconds after instillation before evaluating TFBUT. 
 
With the aid of a slit-lamp, the examiner will monitor the integrity of the tear film, noting 
the time it takes to form micelles from the time that the eye is opened. TFBUT will be 
measured in seconds using a stopwatch for the right eye followed by the left eye. The two 
TFBUT values that are used to calculate the average will be entered into the eCRF. 
 
For each eye, two measurements will be taken and averaged unless the two measurements 
are >2 seconds apart and are each <10 seconds, in which case, a third measurement would 
be taken and the two closest of the three would be averaged. All values will be recorded in 
the source document. 
 
Fluorescein Staining  
The examiner will instill 5 µL of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. Note, this is the same instillation as for 
TFBUT. To thoroughly mix the fluorescein with the tear film, the subject will be instructed 
to blink several times. The examiner should wait approximately 2-3 minutes after 
instillation before evaluating fluorescein staining. A Wratten #12 yellow filter will be used 
to enhance the ability to grade fluorescein staining. The staining will be graded with the 
NEI Grading Scale. Only the cornea will be graded. Digital images of fluorescein staining 
may be taken for digital analysis. 


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NEI/Industry Workshop Scale 
For each eye, score each of the five areas of the cornea. 
 
 
 
Diagram of the division of the corneal surface for measuring fluorescein uptake. A standardized grading 
system of 0-3 is used for each of the five areas on each cornea. Grade 0 will be specified when no staining is 
present. The maximum total score for each eye is 15. 
 
 
Meibomian Gland Assessment (MGD score) 
Meibomian gland dysfunction (MGD) is blockage or some other abnormality of the 
meibomian glands causing an insufficient secretion of lipids into the tear film. This causes 
the tears to evaporate too quickly, and thus MGD is considered a leading cause of dry eye 
syndrome. 
 
The Meibomian Gland Evaluator stick (Korb MGE®-Stick) with standardized force 
application will be used for this assessment. The Meibomian Gland Assessment (MGD 
Score) will be performed during the trial at Visits 1 (transferred from V4 of NVU-003), 2, 
3, 4, 5 and 6 or at an Early Termination Visit.  
 
The secretion of 5 central glands on the lower eyelid will be evaluated for each eye. Each 
of the 5 glands will be scored from 0-3: 0 = normal, 1 = thick/yellow, whitish, 
particulate; 2 = paste; 3 = none/occluded. The total score will thus range from 0-15. 
 
In the NVU-003 study, i.e. as described in the subject’s inclusion criteria, Meibomian 
Gland Dysfunction is defined as MGD score ≥ 3. 
 
 


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Schirmer’s Test I (without anesthesia) 
Schirmer Tear Test I will be performed during the trial at Visits 1 (transferred from V4 of 
NVU-003), 4, and 6, or at an Early Termination Visit.  The test will be performed ≥5 
minutes after MGD evaluation according to the following procedure: 
• Do not blot eyes prior to the test. 
• Using a sterile Schirmer test strip, a bend in the strip will be made in line with the 
notch in the strip. 
• The subject will be instructed to gaze up and in. 
• The Schirmer test strip will be placed in the lower temporal lid margin of each eye 
such that the strip fits tightly. Subjects will be instructed to close their eyes. 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the 
moistened area will be recorded (mm) for each eye. 
 
Procedure for Evaluating Intraocular Pressure 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg at Visits 1 (transferred from V4 of 
NVU-003), 2, 3, 4, 5 and 6, or at an Early Termination Visit. A single measurement will be 
made to obtain a determination of IOP. The same tonometer employing the investigator’s 
standard technique should be used throughout the trial. In addition, all reasonable efforts 
will be made to have the same examiner obtain all IOP measurements for a given subject. 
 
Procedure for Conducting Dilated Fundoscopy 
A dilated fundoscopy exam will be performed during the trial at Visits 1 (transferred from 
V4 of NVU-003), 3, 4, 5 and 6 or at an Early Termination Visit. Observations will be graded 
as Normal or Abnormal. Abnormal findings will be described. The following will be 
examined: 
• Vitreous 
• Retina 
• Macula 
• Choroid 
• Optic Nerve 
 
 
 


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Eyedrop Comfort and Acceptability Questionnaire 
Eyedrop Comfort and Acceptability (4 Questions) will be scored on a visual analog scale 
ranging from 0 to 10. It will be assessed at Visit 6 (or an Early Termination visit) using the 
following Scale: 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
↑ 
↑ 
None/Not 
      Much/Very 
 
Questionnaire Items 
1. How satisfied are you with the study eye drop? 
2. How comfortable did you find the study eye drop? 
3. How easy was the administration of the study eye drop? 
4. How high is the likelihood that you would ask for prescription of the study eye 
drops? 
 
 
 


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At-Home Dosing Diary 
Subjects will be instructed how to complete the dosing diary and asked to complete a dosing 
diary entry for each dose taken daily. 
 
 
Date 
DD/MMM/YYYY   
Morning  
  
Midday 
Afternoon/ 
Early Evening 
At Bedtime 
Subject  
Initials 
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  
___ /____ / _____ 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
q  Yes  
q No 
  


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Telephone calls: Non-leading AE questioning  
The telephone calls are planned to check in with subjects about possible adverse events and 
any changes in medications throughout the study duration.  
 
During the calls the following non-leading questions should be asked: 
 
1. Does the subject take the study medication as prescribed. 
2. Are there changes to the subjects` concomitant medication.  
3. Does the subject experience any health problems.  
 
Appendix 4 
Amendment Summary of Changes  
 
The Purpose of Protocol Amendment 2 dated 04 February 2020 (Protocol Version 3.0) is 
to implement updates and clarify several inconsistencies that are listed in the table below.  
Minor administrative corrections are not listed in the table below. 
Section 
Original Text 
Amended Text (in bold) 
Rationale 
Header 
13 December 2019 FINAL v2.0 
12 March 2020 FINAL v3.0 
New version of 
protocol 
Page 1 
Version 2.0 
Version 3.0 
New version of 
protocol 
Page 1 
(Added) 
Amendment 2: 12 MAR 2020 
Generation of 
amendment 2 
Page 2 
Director 
Clinical 
Ophthalmol
ogy 
Daniela Willen, PhD 
Tel: (0049) 6221-50259-142 
dwillen@novaliq.com 
Exc. 
Director 
–Clinical 
Affairs 
Jason Vittitow, PhD 
Tel: 908-541-3060 
Jason.Vittitow@bausch.com 
Sponsor 
transfer 
Manager 
Clinical 
Operations 
Anja Lange, Dipl.-Biol. 
Tel: (0049) 6221-50259-269 
alange@novaliq.com 
Sr. 
Clinical 
Trial 
Manager 
Dan Donatello 
Tel: 585-338-5306 
Daniel.donatello@Bausch.com 
Page 2 
Clinical 
Project 
Manager: 
Kristie Veasey 
Tel: (001) 919-595-0254 
Fax: (001) 919-640-1663 
Kristie.veasey@lexitas.com 
Nicole Derthick 
Tel: 919-699-9629 
Fax: 919-640-1663 
Nicole.Derthick@lexitas.com  
Project 
manager 
change 
Page 12, 
Abbreviations 
 
IMP Investigational Medicinal 
Product 
Added 
Page 15 
Summary of known and potential 
risks and benefits to human 
subjects 
 
Section 
Deleted; as this 
information is 
present in the 
IB. 
Page 4 and 19, 
Inclusion 
Criteria 
Subjects must: 
1. Have completed trial NVU-
003 without major protocol 
deviations 
2. Have a subject reported 
history of DED in both eyes 
Subject Must: 
1. Have completed trial NVU-
003 without major protocol 
deviations, and have been 
compliant with NVU-003 
Added wording 
from inclusion 
criterion #3 to 
inclusion 
criterion #1.   


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb, Inc. 
Clinical Trial Protocol # NVU-004 
12 March 2020 FINAL v3.0  
 
Confidential 
Page 59 of 64 
for at least 6 months prior to 
Visit 0 of NVU-003 and be 
diagnosed with DED at 
Visit 1 of NVU-003. 
3. Have been compliant with 
trial procedures and 
investigational product in 
NVU-003 according to the 
investigator`s assessment. 
4. Provide written informed 
consent.  
5. Be able and willing to follow 
instructions, including 
participation in all trial 
assessments and visits. 
trial procedures and 
application of IMP. 
2. Have a subject reported 
history of DED in both eyes 
for at least 6 months prior to 
Visit 0 of NVU-003 and be 
diagnosed with DED at 
Visit 1 of NVU-003. 
3. Provide written informed 
consent. 
4. Be able and willing to follow 
instructions, including 
participation in all trial 
assessments and visits. 
Page 26, 
Section 8.1 
In case clinical judgment 
considers it necessary, treatment 
with topical steroids (such as 
loteprednol etabonate, as 
recommended, not longer than 4 
weeks at a time) or other topical 
prescription medications (such as 
cyclosporine, lifitegrast or serum 
tears) are allowed according to 
clinicians` prescription. Their use 
will be documented in the 
subject’s source document and 
corresponding eCRF. 
In case clinical judgment 
considers it necessary, treatment 
with topical steroids (such as 
loteprednol etabonate, as 
recommended, not longer than 
4 weeks at a time) or other 
topical prescription medications 
(such as cyclosporine, lifitegrast 
or serum tears) are allowed 
according to clinicians` 
prescription. Their use will be 
documented in the subject’s 
source document and 
corresponding eCRF. 
Removed 
specific drug 
names as 
deemed not 
necessary to 
provide this 
level of detail. 
Page 30, 
Section 8.6.2 
• Adverse events;  
• Protocol violations;  
• Lack of efficacy;  
• Administrative reasons (e.g. 
inability to continue, lost to 
follow up);  
• Sponsor termination of trial;  
• Subject choice (e.g. withdrawal 
of consent);  
• Other  
•Adverse event; 
•Lack of efficacy; 
•Withdrawal by subject; 
•Protocol violation; 
•Lost to follow up; 
•Sponsor termination of trial; 
•Death 
•Other 
Updated list to 
match CRF 
reasons for d/c. 
Page 38, 
Section 10.1 
Data will be summarized by 
treatment group as assigned in 
NVU-003 and overall. Group 1 
and group 2 consist of subsets of 
subjects who received masked 
treatment with NOV03 or saline, 
respectively, in NVU-003. 
Data will be summarized by 
treatment group as received in 
NVU-003 and overall. Group 1 
and group 2 consist of subsets of 
subjects who received masked 
treatment with NOV03 or saline, 
respectively, in NVU-003. 
Updated by 
stats 
Page 38, 
Section 10.3 
Therefore, with 100 subjects 
completing week 52 (or week 26) 
of treatment, if an adverse event 
of a specific type is not observed, 
Therefore, with 100 subjects 
completing week 52 (or week 
26) of treatment, if an adverse 
event of a specific type is not 
Deleted by stats 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb, Inc. 
Clinical Trial Protocol # NVU-004 
12 March 2020 FINAL v3.0  
 
Confidential 
Page 60 of 64 
then with 95% confidence, the 
true incidence rate of the adverse 
event is less than 3.0%. 
observed, then with 95% 
confidence, the true incidence 
rate of the adverse event is less 
than 3.0%. 
Page 39, 
Section 10.4.1 
 
The results of assessments 
performed at multiple visits will 
be presented by visit as 
appropriate unless otherwise 
specified. 
The results of bilateral ocular 
assessments will be summarized 
separately for study and fellow 
eyes. 
Added by stats 
Page 39, 
Section 10.4.5 
Dosing information will be 
summarized overall and by 
treatment from NVU-003 and 
listed for each subject. 
Discontinuation of treatment will 
be summarized. The primary 
reason for IMP discontinuation 
will also be summarized by 
treatment group as assigned in 
NVU-003. Adverse events (AEs) 
will be coded using the MedDRA 
dictionary. An AE is treatment 
emergent if it occurs or worsens 
after the first dose of trial 
treatment in clinical trial NVU-
004.  
Frequencies and percentages of 
subjects with TEAEs, treatment 
related TEAEs, serious TEAEs, 
and TEAEs causing premature 
discontinuation will be provided.  
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.  
 
Dosing information will be 
summarized overall and by 
treatment from NVU-003 and 
listed for each subject. 
Discontinuation of treatment will 
be summarized. The primary 
reason for IMP discontinuation 
will also be summarized by 
treatment group as received in 
NVU-003. Adverse events (AEs) 
will be coded using the MedDRA 
dictionary. An AE will be 
defined as treatment emergent if 
it occurs or worsens after the first 
dose of trial treatment in clinical 
trial NVU-004.  
Frequencies and percentages of 
subjects with TEAEs, treatment 
related TEAEs, serious TEAEs, 
and TEAEs causing premature 
discontinuation will be provided.  
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 provided for 
ocular and non-ocular AEs.  
Ocular AEs will be summarized 
at the subject level, at the eye 
level and separately for study 
and fellow eyes.  
Updated by 
stats 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb, Inc. 
Clinical Trial Protocol # NVU-004 
12 March 2020 FINAL v3.0  
 
Confidential 
Page 61 of 64 
Page 40 
Other safety endpoints including 
those assessed by visual acuity, 
slit-lamp biomicroscopy, dilated 
fundoscopy, and intraocular 
pressure will be summarized by 
visit and by treatment group as 
assigned in NVU-003 using 
descriptive statistics. Changes 
from baseline (as defined in 
clinical trial NVU-003) will also 
be summarized where 
appropriate. For assessments 
performed by eye, study eye and 
fellow eye will be summarized 
separately.  
Other safety endpoints including 
those assessed by visual acuity, 
slit-lamp biomicroscopy, dilated 
fundoscopy, and intraocular 
pressure will be summarized by 
visit and by treatment group as 
received in NVU-003 using 
descriptive statistics. Changes 
from baseline (baseline as 
defined in clinical trial NVU-003) 
will also be summarized where 
appropriate. For assessments 
performed by eye, study eye and 
fellow eye will be summarized 
separately.  
Updated by 
stats 
Section 4.3 
The results of assessments at 
Visit 4 (Day 57) in study NVU-
003 (=final visit) will be taken as 
Day 1 data for NVU-004. Further 
data/assessments to be captured 
will be the NVU-004 Informed 
Consent, Inclusion/Exclusion 
Criteria to determine NVU-004 
eligibility, and IMP dispensation. 
 
The results of assessments at 
Visit 4 (Day 57) in study NVU-
003 (=final visit) will be taken as 
Day 1 data for NVU-004. Further 
data/assessments to be captured 
will be the NVU-004 Informed 
Consent, Inclusion/Exclusion 
Criteria to determine NVU-004 
eligibility, Non-leading Adverse 
Event questioning (AE query) 
and IMP dispensation. 
Clarification of 
requirements at 
Visit 1. 
Appendix 1, 
Visit 1 (Day 
1) 
Adverse Event Query 
X
3 
Adverse Event Query 
X4 
Clarification of 
requirements at 
Visit 1. 
Appendix 3, 
MGD Score 
on page 55 
In this study, i.e. as described in 
the subject’s inclusion criteria, 
Meibomian Gland Dysfunction is 
defined as MGD score ≥ 3. 
In the NVU-003 study, i.e. as 
described in the subject’s 
inclusion criteria, Meibomian 
Gland Dysfunction is defined as 
MGD score ≥ 3. 
Clarification 
that MGD 
score is 
evaluated for 
inclusion at 
NVU-003 only. 
Appendix 3, 
Procedure for 
Evaluating 
IOP on page 
56 
Intraocular pressure (IOP) will be 
measured in each eye by contact 
tonometry by the examiner and 
the results will be recorded in 
mmHg at Visits 0 and 4, and at an 
Early Termination Visit. 
Intraocular pressure (IOP) will be 
measured in each eye by contact 
tonometry by the examiner and 
the results will be recorded in 
mmHg at Visits 1 (transferred 
from V4 of NVU-003), 2, 3, 4, 5 
and 6, and at an Early 
Termination Visit. 
Clarification of 
visit schedule 
for IOP 
assessment. 
Appendix 3, 
Procedure for 
Conducting 
Dilated 
Fundoscopy 
A dilated fundoscopy exam will 
be performed during the trial at 
Visits 0 (Screening) and 4 and at 
an Early Termination Visit. 
A dilated fundoscopy exam will 
be performed during the trial at 
Visits 1 (transferred from V4 of 
NVU-003), 3, 4, 5 and 6 and at 
an Early Termination Visit. 
Clarification of 
visit schedule 
for Dilated 
Fundoscopy 
assessment. 


NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb, Inc. 
Clinical Trial Protocol # NVU-004 
12 March 2020 FINAL v3.0  
 
Confidential 
Page 62 of 64 
Appendix 3, 
Eyedrop 
Comfort and 
Acceptability 
Questionnaire 
Eyedrop Acceptability 
Questionnaire 
Eyedrop Acceptability (3 
Questions) will be scored on a 
visual analog scale ranging from 
0 to 10. It will be assessed at Visit 
4 using the following Scale: 
Questionnaire Items 
1. How satisfied are you with 
the study eye drop? 
2. How easy was the 
administration of the study 
eye drop? 
3. How high is the likelihood 
that you would ask for 
prescription of the study eye 
drops? 
 
Eyedrop Comfort and 
Acceptability Questionnaire 
Eyedrop Comfort and 
Acceptability (4 Questions) will 
be scored on a visual analog scale 
ranging from 0 to 10. It will be 
assessed at Visit 6 (or at an 
Early Termination Visit) using 
the following Scale: 
Questionnaire Items 
1. How satisfied are you with 
the study eye drop? 
2. How comfortable did you 
find the study eye drop? 
3. How easy was the 
administration of the study 
eye drop? 
4. How high is the likelihood 
that you would ask for 
prescription of the study eye 
drops? 
Clarification of 
visit schedule. 
Name change 
and question 
added. 
Appendix 5 
(Added) 
Amendment 2: 12 MAR 2020 
Generation of 
Amendment 2 
Appendix 5 
Sponsor signatories from Novaliq 
(Daniela Willen, Anja Lange, 
Sonja Krösser, PhD, Gabriela 
Burian) and Lexitas (Kristie 
Veasey) 
Sponsor signatories from B+L 
(Johnson Varughese, Jason 
Vittitow, Gary Mosehauer, 
Robert Kang, Mary Harrell, Binu 
Alexander) and Lexitas (Joanna 
Williams) 
Change of 
contacts for 
study 
Appendix 6 
(Added) 
Amendment 2: 12 MAR 2020 
Generation of 
Amendment 2 
 
 
 




NOV03 (100% Perfluorohexyloctane) 
Sponsor: Bausch & Lomb, Inc. 
Clinical Trial Protocol # NVU-004 
12 March 2020 FINAL v3.0  
 
Confidential 
Page 64 of 64 
Appendix 6 Investigator’s Signature 
 
Protocol Title: 
A Phase 3, Multi-Center, Open-Label Extension (OLE) Clinical 
Trial to Assess the Extended Long-Term Safety and Tolerability 
of NOV03 (Perfluorohexyloctane) in Subjects who Completed 
Trial NVU-003 (Kalahari OLE) 
Protocol Number: 
NVU-004 
Date: 
Amendment 1 
14 OCT 2019 
13 DEC 2019 
 
Amendment 2 
12 MAR 2020 
I agree to implement and conduct the trial diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to maintain 
all information supplied by CRO and the sponsor in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Ethical Review Committee (ERC) or 
another group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number: