Randomized, Controlled, Single-Center, Cross-Over Clinical Study to Evaluate Tear Characteristics Following Acute TrueTear™ Use
Phase: NA
Conditions: Dry Eye Syndromes
Sponsor: Allergan

NCT03274999 
 
Study ID: OCUN‐020 
 
 
Title:  Randomized, Controlled, Single‐Center, Cross‐Over Clinical Study to Evaluate Tear Characteristics 
Following Acute TrueTear™ Use 
 
Protocol Date: 09Aug2017 
 
 
 
 

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ALLE RGAN CONFI DENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
Randomized, Controlled, Single-Center, Cross-Over Clinical Study to 
Evaluate Tear Characteristics Following Acute TrueTear™ Use 
Protocol Number: 
OCUN-020   
Protocol Date:  
May 22, 2017 
Device Name: 
TrueTear™ 
Sponsor: 
Allergan (North America)  
 
 
 
Site: 
 
 
 
 
 
 
 
 

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STUDY ADMINISTRATION 
 
MEDICAL MONITOR 
 
 
 
 
 
SPONSOR PERSONNEL 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
SITE PERSONNEL 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SYNOPSIS 
Protocol Title: 
Randomized, Controlled, Single-Center, Cross-Over Clinical 
Study to Evaluate Tear Characteristics Following Acute 
TrueTear™ Use 
Protocol Number: 
OCUN-020 
Study Device(s): 
TrueTear™ (Intranasal Tear Neurostimulator) CE marked and 
to be used as per its intended use. 
Study Objective: 
The primary objective of this study is to compare the change in 
tear meniscus height (TMH) (immediately post versus pre-
application) produced by intranasal stimulation with TrueTear 
versus the same device applied extranasally (control). In 
addition, this study will also: 
 Compare the duration of change in TMH (post versus 
pre-application) produced by intranasal versus 
extranasal (control) application of TrueTear 
 Compare the change and duration of change (post 
versus pre-application) in lipid layer thickness (LLT) 
produced by intranasal versus extranasal (control) 
application of TrueTear 
 Compare the change and duration of change (post 
versus pre-application) in non-invasive tear film break-
up time (NITBUT), protective index and exposed area 
produced by intranasal versus extranasal (control) 
application of TrueTear  
Overall Study Design 
Structure: 
Prospective, randomized, single-center, cross-over design 
comparing the effect of intranasal versus extranasal (control) 
stimulation with TrueTear 
Duration: 
Participation is expected to last up to 50 days for each 
participant  
Control: 
Extranasal stimulation 
Device Regimen: 
There are two applications of TrueTear planned, one intranasal 
(test) and one extranasal (control). Participants will receive 
both applications, in random sequence, one at each of the two 
application days (Visit 2 and Visit 3). The two applications 
consist of: 
•  Active intranasal device application for a duration of 
approximately 3 minutes  
• 
Active but extranasal device application (control) for a 
duration of approximately 3 minutes 

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Visit Schedule: 
Visit 1: Screening (Day -14 (±11days)) 
Visit 2: First application (Day 0) 
Visit 3: Second application / Exit (Day 14 (±11 days)) 
Study Population Characteristics 
Number of Participants: 
Approximately 35 participants with dry eye will be enrolled at 
one site in the UK in two groups: an initial 10 participants and 
a second group of 25 participants to be enrolled following an 
interim analysis. 
Condition/Disease: 
Dry Eye Disease (DED) 
Evaluation Criteria 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
General Statistical Methods and Types of Analyses 
Sample Size 
Approximately 35 completed participants will be enrolled. This is an exploratory study and 
no formal sample size calculation was performed.   
 
 
 
 
  
 
 
 
 
 
 

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TABLE OF CONTENTS 
STUDY SYNOPSIS ........................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................6 
TABLE OF FIGURES .....................................................................................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
Introduction ..........................................................................................................................9 
1.1. 
Background ..........................................................................................................9 
1.2. 
Rationale ............................................................................................................10 
2. 
Study Objectives ................................................................................................................10 
3. 
Clinical Hypotheses ...........................................................................................................11 
4. 
Overall Study Design .........................................................................................................11 
5. 
Study Population ................................................................................................................13 
5.1. 
Inclusion Criteria ...............................................................................................13 
5.2. 
Exclusion Criteria ..............................................................................................13 
5.3. 
Inclusion/Exclusion Exceptions .........................................................................14 
5.4. 
Discontinuation Criteria (if applicable) .............................................................14 
6. 
 
 
 
 
 
 
 
7. 
Device Description.............................................................................................................16 
7.1. 
Study Device ......................................................................................................16 
7.2. 
Device Accountability .......................................................................................17 
7.3. 
Comparator Application Arms ...........................................................................17 
7.4. 
Other Study Supplies .........................................................................................18 
8. 
Study Methods and Procedures ..........................................................................................18 
8.1. 
Participant Entry Procedure ...............................................................................18 
8.2. 
Masking and Dispensing ....................................................................................19 
8.3. 
Participant Training and Dispensing of Device .................................................19 
8.4. 
Concurrent Therapies .........................................................................................21 
8.5. 
Examination Procedures ....................................................................................21 
8.6. 
Schedule of Visits ..............................................................................................23 
8.7. 
Participant Accountability .................................................................................24 
8.8. 
Study Termination .............................................................................................24 
8.9. 
Study Duration ...................................................................................................25 
8.10. 
Monitoring and Quality Assurance ....................................................................25 
9. 
Adverse Events ..................................................................................................................26 
9.1. 
Adverse Event Recording ..................................................................................26 

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9.2. 
Adverse Event Evaluation..................................................................................26 
9.3. 
Relationship of the AE to the study device ........................................................27 
9.4. 
Serious and Unanticipated Adverse Device Effects ..........................................27 
9.5. 
Adverse Event Reporting ...................................................................................27 
9.6. 
Anticipated Adverse Events ...............................................................................28 
10. 
Pregnancy ...........................................................................................................................29 
11. 
Statistical Hypothesis and Methods of Analyses ...............................................................30 
11.1. 
Power Calculation and Determination of Sample Size ......................................30 
11.2. 
Statistical Hypotheses and Level of Significance ..............................................30 
11.3. 
Randomization ...................................................................................................30 
11.4. 
Evaluability of Data ...........................................................................................30 
11.5. 
General Statistical Considerations .....................................................................31 
11.6. 
Participant Accountability and Missing Data ....................................................31 
11.7. 
Participant Demographic and Baseline Characteristics .....................................31 
11.8. 
Effectiveness Analyses ......................................................................................31 
 
 
 
 
 
 
12. 
Final Clinical Study Report ...............................................................................................32 
13. 
Compliance with Good Clinical Practices, Ethical Considerations, and Administrative 
Issues ..................................................................................................................................32 
13.1. 
Protection of Human Participants ......................................................................32 
13.2. 
Documentation ...................................................................................................33 
13.3. 
Regulatory Status ...............................................................................................33 
13.4. 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Device ......................................................................................................33 
13.5. 
Recording of Data on Source Documents and Case Report Forms (eCRFs) ....34 
13.6. 
Amendments to the Protocol ..............................................................................34 
13.7. 
Publications ........................................................................................................34 
14. 
References ..........................................................................................................................35 
15. 
Appendices .........................................................................................................................36 
 
  
 
15.2. 
Appendix 2: Examination Procedures, Tests, Equipment and Techniques .......37 
 
 
15.4. 
Appendix 4: Investigator’s Signature ................................................................44 
 
 
 

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TABLE OF FIGURES 
Figure 1  TrueTear Components .................................................................................................. 16 
Figure 2  Use of TrueTear (L) Starting position and (R) Correct treatment position by inserting 
the tips fully into the nasal cavity ................................................................................. 20 
Figure 3  Schematic showing location of Tip Assembly application for control (extranasal) 
application of TrueTear ................................................................................................ 20 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ADE 
Adverse device effect 
BCVA 
Best corrected distance visual acuity 
CI 
Confidence interval 
DED 
Dry eye disease 
CRF 
Case report form 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
EMS 
Electro-neuromuscular stimulation 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
LED 
Light-emitting diode 
LFU 
Lacrimal functional unit 
LLT 
Lipid layer thickness 
logMAR 
Logarithm of the minimum angle of resolution 
Mm 
Millimeter 
NITBUT 
Non-invasive tear film break-up time 
OSDI© 
Ocular Surface Disease Index© 
OTC 
Over-the-counter 
PP 
Per protocol 
SAE 
Serious adverse event 
TENS 
Transcutaneous electrical nerve stimulation 
TMH 
Tear meniscus height 
US 
United States 
WOCBP 
Women of childbearing potential 
 
 
 
 
 

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1. INTRODUCTION 
1.1. 
BACKGROUND 
The 2007 National Eye Institute (NEI)/Industry Dry Eye Workshop defined dry eye disease 
(DED) as a multifactorial disease of the tears and ocular surface that results in symptoms of 
discomfort, visual disturbance, and tear film instability with potential damage to the ocular 
surface.1 DED has a complex pathophysiology and a multifactorial etiology related to an 
inadequacy of one or more layers of the tear film. It is accompanied by increased osmolarity of 
the tear film and inflammation of the ocular surface.1 An estimated 25 million Americans are 
reported to have DED, one of the most common reasons patients seek care with their eye care 
professional.1,2    
DED is recognized as a disturbance of the Lacrimal Functional Unit (LFU), an integrated system 
comprised of the lacrimal glands, ocular surface (cornea, conjunctiva) and lids (meibomian 
glands), and the sensory and motor nerves that connect them.3 This functional unit controls the 
major components of the tear film in a regulated fashion and is responsive to environmental, 
endocrinological, and cortical influences. Its general function is to preserve tear film integrity, 
corneal transparency, and the image quality projected onto the retina.4-6  
Signs of DED include reduced tear volume, delayed tear clearance, abnormal tear osmolarity, 
decreased tear film break-up time, punctate keratitis and distorted mires on keratometry or 
corneal topography. Symptoms can include dryness, grittiness, burning, stinging, discomfort, 
photophobia, redness, tearing, reduced ability for prolonged reading or computer work and 
fluctuating vision. These symptoms are typically worse later in the day and can be triggered or 
exacerbated by environmental conditions such as low humidity or wind. 
The severity and prevalence of DED in the general population increases with age and is 
particularly common in post-menopausal women and in those 65 and older. While patients with 
mild to moderate DED experience a range of complaints, as described above, patients with 
severe DED are at risk for more serious ocular findings, such as punctate keratopathy evidenced 
by significant fluorescein staining of the cornea and epithelial defects. More severely affected 
patients can experience a quality of life deficiency comparable to that of moderate to severe 
angina.7 
Studies suggest that dry eye can be associated with significant impact on visual function, including 
reading and driving8 as well as daily activities, social and physical functioning, workplace 
productivity, and quality of life.5  
 
Treatment for DED is generally palliative in nature and intended to supplement patients’ natural 
tears or to improve the residence time of a limited volume of tears. Depending on the severity of 
disease and the underlying etiology of the DED, treatment options include artificial tear 
substitutes (solutions, ointments, and gels), punctal plugs, warm compresses, environmental 
modification, omega-3 fatty acid supplements, and moisture chamber goggles.8,9 For patients 

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with an inflammatory component to their DED, topical cyclosporine (RESTASIS®; Allergan) or 
lifitegrast (Xiidra®; Shire) are treatment options and an eyelid thermal pulsation system 
(Lipiflow Thermal Pulsation System; Tearscience, Inc.) can be used by patients with evaporative 
dry eye or lipid deficient dry eye. Patients with more severe disease may be treated with punctal 
cautery, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, 
autologous serum tears, Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) 
scleral contact lenses and tarsorrhaphy.   
1.2. 
RATIONALE 
The nasolacrimal reflex is a well-established pathway by which nasal stimuli promote both 
resting basal10 and bolus tear secretion. The reflex plays a functional role in expelling foreign 
bodies or irritants from the nose by secreting tears into the nasal cavity via the nasolacrimal duct 
upon stimulation by the irritant.   
Reflex activation of the lacrimal glands is also one of the body’s primary compensatory 
mechanisms for addressing ocular surface dryness. Unfortunately, over time, an arid 
environment and resulting inflammation results in damage to the afferent nerves innervating the 
cornea, compromising the reflex response and ultimately leading to an even drier ocular surface. 
Studies have demonstrated that intranasal stimulation via use of the TrueTear device results in a 
statistically significant increase in tear production measured by the Schirmer test11,12 and as such 
may provide a novel option for the treatment of DED. However, to date, the duration of increased 
tear secretion post TrueTear use has not been quantified. Thus this study is aimed at quantifying 
both the acute change and duration of change of tear secretion post-use of TrueTear. In addition, 
the quality of the secreted tears will be characterized through measures of lipid layer thickness and 
break-up time. Altogether, this study should provide significant insight into the nature and duration 
of acute tear secretion associated with TrueTear application.   
2. STUDY OBJE CTIVES 
The primary objective of this study is to compare the change in tear meniscus height (TMH) 
(immediately post versus pre-application) produced by intranasal application of TrueTear (test) 
versus the same device applied extranasally (control). In addition, this study will also: 
 Compare the duration of change in TMH (post versus pre-application) produced by 
intranasal (test) versus extranasal (control) application of TrueTear 
 Compare the change and duration of change (post versus pre-application) in lipid layer 
thickness (LLT) produced by intranasal (test) versus extranasal (control) application of 
TrueTear 
 Compare the change and duration of change (post versus pre-application) in non-invasive 
tear film break-up time (NITBUT), protective index and exposed area produced by 
intranasal (test) versus extranasal (control) application of TrueTear 

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3. CLINICAL HYPOTH ESES 
The clinical hypothesis for this study is that the difference in TMH measured pre-application and 
immediately post-application in the study eye between the two applications (intranasal vs 
extranasal control) will be statistically significantly greater in favor of intranasal stimulation.  
Additionally, the difference in the change of the lipid layer thickness measured pre-application 
and immediately post-application in the study eye between the two applications (intranasal vs 
extranasal control) will be statistically significantly greater in favor of intranasal stimulation.  
4. OVERALL STUDY DESIGN 
This is a prospective, randomized (order of the test and control applications), cross-over design 
comparing the effect of intranasal (test) versus extranasal (control) stimulation with TrueTear on 
change in tear meniscus height (TMH) and duration of this change. Additionally, the change and 
duration of change in the lipid layer thickness (LLT), non-invasive tear film break-up time 
(NITBUT), protective index and exposed area caused by intranasal versus extranasal (control) 
stimulation with TrueTear will be evaluated. 
The study will be carried out in two phases: an initial phase involving 10 participants who have 
provided informed consent and have met the eligibility criteria and a second phase following an 
Interim Data Analysis involving the remainder of the population of up to a total of 25 additional 
participants who have met the same criteria. 
At the completion of the initial phase, an interim analysis will be carried out to obtain a first 
indication of the duration of the changes that are being measured. The test visit protocol sets the 
follow-up visits post application at six hours, based upon information obtained during previous 
clinical studies. However, the exact duration of the effect is unknown and this exploratory study 
may demonstrate that the effect is of a shorter or longer duration. Hence, to avoid unnecessary 
burden to participants, if the effect is of shorter duration than six hours or to optimize the 
scientific validity of the study if the effect is of a longer duration, the follow-up period will be 
reviewed and potentially modified. There is no plan to stop this study based on the results of the 
Interim Data Analysis.  
The two-phase approach optimizes the protocol and allows for any potential change to receive 
ethics approval before implementation. At the completion of the initial phase, the Ethics 
Committee will be either informed that the follow-up period remains unchanged and the study 
continues under the current protocol or that a change to the protocol will be submitted for review 
that will be limited to the duration of the follow-up period and timing of the post application 
measurements.; The corresponding information to participants and consent forms will also be 
submitted for approval. 
 
 

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Participants who terminate early during the application period will be asked to complete safety 
assessments (if the participants agree) prior to study exit. Participants who are terminated early 
from the study will not be replaced. 
5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
1. Eighteen (18) years of age or older 
2. Baseline OSDI© score of at least 23 with no more than three responses of “not applicable”  
3. In at least one eye, a baseline Schirmer test of ≤ 10 mm/5 minutes AND a cotton swab 
nasal stimulation Schirmer test of at least 7 mm higher in the same eye 
 
 
 
 
 
 
5.2. 
EXCLUSION CRITERIA 
Participants must not: 
1. 
Have chronic or recurrent epistaxis, coagulation disorders or other conditions that, in 
the opinion of the Investigator, may lead to clinically significant risk of increased 
bleeding 
2. 
Have had nasal or sinus surgery (including history of application of nasal cautery) or 
significant trauma to these areas 
3. 
Have a vascularized polyp, severely deviated septum or severe nasal airway obstruction 
as confirmed by intranasal examination performed at the Screening Visit 
4. 
Have had any intraocular surgery (such as cataract surgery), extraocular surgery (such 
as blepharoplasty) in either eye within three months or refractive surgery (e.g. LASIK, 
LASEK, PRK or corneal implant) within twelve months of the Screening Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9. 
Have a cardiac demand pacemaker, implanted defibrillator, or other implanted metallic 
or active implanted electronic device in the head, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
5.3. 
INCLUSION/EXCLUSION EXCEPTIONS 
The investigator has the right to exclude a potential participant’s enrollment in the study if s/he 
deems it in the best interest of the participant. Reasons for exclusion on this basis will be 
recorded. 
5.4. 
DISCONTINUATION CRITERIA (IF APPLICABLE) 
Participants are free to discontinue their participation in this study at any time and for any 
reason, specified or unspecified, without prejudice. In addition, the Investigator may decide to 
discontinue a participant from the study for safety reasons or when it is in the best interest of the 
participant. No constraints will be placed on ordinary patient management.  
Reasons for participant withdrawal may include but are not limited to the following: 
 Either at the Investigator's request, for safety reasons (e.g., serious or severe AE), or at 
the participant’s request. 

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 Non-compliance (e.g., failure to follow application instructions, missing visits, using 
prohibited medications). 
 When a concomitant therapy likely to interfere with the results of the study is reported 
or required by the participant (the Investigator will report all such information on the 
source documents/ case report forms (CRFs) and decide, in accordance with the 
Sponsor, whether the participant is to be withdrawn). 
 A confirmed positive pregnancy test at any time during the study. 
 When a participant is lost to follow-up. The Investigator (or designee) will make every 
attempt to reach the participant by telephone and/or letter before considering the 
participant as lost to follow-up.  
 When a participant is erroneously admitted into the study or does not meet the eligibility 
criteria. 
In addition, the Sponsor also reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
All early discontinuations and their reasons must be carefully documented by the Investigator on 
the End of Study CRF and, if applicable, on the Adverse Event (AE) CRF. No participant who 
has been randomized can be replaced by another participant if the participant is discontinued 
prematurely for any reason. 
6. 
STUDY PARAMETERS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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7. 
DEVICE DESCRIPTION 
7.1. 
STUDY DEVICE 
The TrueTear device delivers small electrical currents to the inner cavity of the nose, activating 
nerves that stimulate the body’s natural tear production system.  The device is CE marked and 
will be used in this study as per its intended use. 
The device consists of four distinct parts (Figure 1): 
1. A reusable Base Unit which produces the electrical stimulation waveform. 
2. A disposable Tip that inserts into the nasal cavity and stimulates the target intranasal 
tissue. 
3. A reusable Cover to protect the Tip.  
4. A Charger which recharges the battery inside the Base Unit. 
 
 
Base Unit with Cover 
Base Unit with the Disposable Tips 
 (Front and Back) 
 
TrueTear System 
Figure 1  TrueTear Components 

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7.1.1. 
 Base Unit 
When activated, the Base Unit provides electrical pulses to the Tip. The strength of these pulses 
is controlled by two buttons, with five different intensity levels available, indicated by the 
number of illuminated LEDs on the Base Unit. The device internally records the time and 
duration of device use. 
7.1.2. 
Disposable Tip 
The disposable Tip is specially designed to allow the participant to easily apply stimulation to 
the target areas within the nose. The Tip attaches to the Base Unit and contains hydrogel (similar 
to the material used in contact lenses) that contacts the inside of the nose to provide stimulation. 
Each tip may be used up to 24 hours. After 24 hours, the used tip should be discarded and a fresh 
tip should be attached. A separate Cover can be used to protect the Tip and Base Unit when the 
device is not in use. 
7.1.3. 
 Cover 
The Cover may be placed over the top of the Tip attached to the Base Unit for protection in 
between uses.   
7.1.4. 
 Charger 
The Base Unit may be recharged by removing the Tip and placing the Base Unit onto the 
Charger. Charging typically takes under 4 hours, and a green LED indicates that the process has 
completed. 
7.2. 
DEVICE ACCOUNTABILITY 
Each Base Unit has a unique serial number and the serial number of the Base Unit used by each 
participant will be recorded on the appropriate case report form and device accountability log. 
The removable disposable Tip is provided in an air tight sealed pouch, which is labeled with the 
lot number and expiration date. The lot number of the Tip provided to a participant will also be 
recorded on the appropriate case report forms and on the device accountability log.  Tips should 
not be used beyond the expiration date provided on the pouch. 
7.3. 
COMPARATOR APPLICATION ARMS  
The comparator (control) will consist of the use of TrueTear applied externally to the nose where 
the participant may feel some stimulation.  
 
 

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7.4. 
OTHER STUDY SUPPLIES 
The following will be provided by Allergan: 
 Urine pregnancy test kits 
 Schirmer test strips 
The following will be provided by the investigator: 
 Proxymetacaine  
8. 
STUDY METHODS AND PROCEDURES 
8.1. 
PARTICIPANT ENTRY PROCEDURE 
8.1.1. 
Overview 
Participants who meet all inclusion and exclusion criteria will be considered for entry into this 
study. 
8.1.2. 
Informed Consent 
Prior to a participant’s participation in the trial (i.e., prior to study-related procedures), the study 
will be discussed with each potential participant and participants wishing to participate must give 
written informed consent using an Ethics Committee approved informed consent form (ICF).  
The prospective participants will be selected from the existing clinical population of the 
 
 or recruited my means of an advertisement if necessary. The participants 
fulfilling the criteria for inclusion and none of the exclusion criteria, will be invited in a random 
fashion to participate in the study until the test population is achieved. 
The prospective participants will initially be contacted by telephone, the investigation will be 
explained in detail and if interested a screening / enrolment visit will be scheduled. The 
prospective participants will be sent a copy of the Participant Information Sheet and Informed 
Consent by email prior to the visit and will be asked to read and the Informed Consent to sign 
prior to any evaluation. 
 
  
 
 
 
 
 
 
 
 
  
 
  

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 
  
 
8.1.4. 
Procedures for Final Study Entry 
Participants must meet all inclusion and none of the exclusion criteria to qualify for enrollment 
 
8.1.5. 
Methods for Assignment to the Order of Use of the Test and Control 
Applications 
Each participant who qualifies for entry at Visit 1 will be assigned a screening number.  All 
screening numbers will be a three-digit number starting with 
 assigned in strict numerical 
sequence at the site and no numbers will be skipped or omitted.  The site number will precede 
the screening number in the fashion of 
.   
If all inclusion and exclusion criteria are met at Visit 1, each qualifying participant will be 
assigned an enrollment randomization number at Visit 1. Enrollment randomization numbers will 
be a 4-digit site specific number assigned in sequential order 
 A 
computer-generated block randomization schedule will be prepared with the application 
sequences to correspond to each randomization number.   
8.2. 
MASKING AND DISPENSING 
On Day 0, participants will receive training by trained clinical staff on the use of TrueTear 
consistent with their randomized assignment (intranasal or extranasal application).  The serial 
number of the unit will be documented in the participant’s CRF and device accountability log. 
The lot number of the tip provided to a participant will also be recorded on the appropriate case 
record form and device accountability log. Participants will remain masked as to which 
application is the active and which is the control. 
8.3. 
PARTICIPANT TRAINING AND DISPENSING OF DEVICE 
Participants will receive training to perform nasal neurostimulation and will undergo stimulation 
for the first time on Day 0. On Day 0, participants will be provided with a TrueTear device and a 
disposable tip.   
For the intranasal application, participants will be instructed to place the tips of TrueTear into 
both nostrils simultaneously towards the top and front of the nose (as in Figure 2). They will be 
told to turn on the unit by holding down the + button for approximately two seconds. There are 
five stimulation intensity levels and participants may adjust the level by pressing the + or – 
buttons to obtain a gentle tingling sensation. Participants will be told they can cease stimulation 
by holding down the – button for approximately two seconds on the Base Unit or by withdrawing 
the tips from the nostrils. Participants will be asked to apply stimulation for approximately three 
minutes. 

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Figure 2  Use of TrueTear (L) Starting position and (R) Correct treatment position by 
inserting the tips fully into the nasal cavity 
 
For the control (extranasal) application, participants will be instructed to place the tips of the 
TrueTear on the lower part of the nose (one tip on each side as in Figure 3). They will be told to 
turn on the unit by holding down the + button for approximately two seconds. There are five 
stimulation intensity levels and participants may adjust the level by pressing the + or – buttons to 
obtain the best tingling sensation. Participants will be told they can cease stimulation by holding 
down the – button for approximately two seconds on the Base Unit or by removing contact with 
the nose. Participants will be asked to apply stimulation for approximately three minutes. 
 
Figure 3  
Schematic showing location of Tip Assembly application for control 
(extranasal) application of TrueTear 

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8.4. 
CONCURRENT THERAPIE S 
The use of any concurrent medication, prescription or OTC, is to be recorded on the participant’s 
CRF along with the reason the medication was taken. Concomitant medications that are considered 
necessary for the participant’s welfare, but will not interfere with study assessments and 
evaluations, will be allowed during the study at the Investigator’s discretion. 
Concurrent enrollment in another investigational drug or device study is not permitted. 
8.5. 
EXAMINATION PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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8.5.4. 
Early Termination/Discontinuation 
If a participant is discontinued from the study prior to Day 0, then all safety evaluations that 
are to be performed on Day 0 should be performed on the day of discontinuation (early 
termination) at the discretion of the Investigator. Participants who are terminated early from 
the study will not be replaced. 
8.6. 
SCHEDULE OF VISITS 
8.6.1. 
Scheduled Visit 
Participants will remain in the study for up to 50 days and will be seen at the following 
intervals: 
 
 
 
 
 
 
 
 
 
 
 
 

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The schedule of exams and procedures performed at these visits can be found in 
Appendix 1.  Descriptions of exams and procedures performed during these visits can be 
found in Appendix 2. 
Participants who are exited from the study due to unanticipated adverse device effects will 
be followed until their medical outcome is determined. The Investigator must provide 
written reports to the study Sponsor. 
8.6.2. 
Unscheduled Visits 
These visits may be performed in order to ensure participant safety. For participants 
reporting for an unscheduled visit, assessments performed are at the discretion of the 
Investigator. At minimum, AEs should be assessed. All procedures performed at an 
unscheduled visit will be recorded on the Unscheduled Visit CRF pages. Any procedure 
indicated in the CRF that is not performed should be indicated as “Not done.” 
8.7. 
PARTICIPANT ACCOUNTABILITY 
8.7.1. 
Completed Participants 
A completed participant is one who has not been discontinued from the study and has 
successfully completed Visits 1 through 3. 
 
8.7.2. 
Discontinued Participants 
Participants may be discontinued prior to their completion of the study due to: 
 
AE 
 
Protocol deviation 
 
Administrative reasons (e.g., inability to continue) 
 
Lost to follow-up 
 
Pregnancy 
 
Sponsor termination of study 
 
Other 
Note: In addition, any participant may be discontinued for any sound medical reason. 
Notification of a participant discontinuation and the reason for discontinuation will be made to 
the Sponsor and will be clearly documented on the participant’s CRF. 
8.8. 
STUDY TERMINATION 
The study may be stopped at any time by the Investigator and/or Sponsor with appropriate 
notification. 

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8.9. 
STUDY DURATION 
An individual participant’s participation will involve up to three visits over a maximum of 50 
days.   
8.10. MONITO RING AND QUALITY ASSURANCE 
8.10.1. Study Monitoring 
 (or designees) will monitor this study in a manner consistent with applicable 
health authority regulations and the procedures adopted by the SOPs of 
.  Prior to the 
start of the study, member(s) of Allergan, Inc. (or designees) will review the protocol, 
CRFs, regulatory obligations, and other material or equipment relevant to the conduct of the 
study with the Principal Investigator/Sub-Investigator(s) and pertinent study staff.  
Monitoring visits will occur as necessary during the course of the investigation to verify: 
 The rights and well-being of participants are protected 
 The conduct of the investigation is in compliance with the currently approved 
protocol/amendment, GCP and IEC requirements 
 The integrity of the data 
 Study device accountability  
 Adequate study documentation 
During the course of the study, if the Sponsor (or designee) determines that the Investigator 
is non-compliant with the study plan and/or applicable regulatory requirements, the Sponsor 
(or designee) will take written action to correct the non-compliance and to secure 
compliance. In addition, the Sponsor (or designee) may terminate the Investigator’s 
participation in the study if appropriate, or if the Investigator remains non-compliant despite 
the Sponsor’s actions. This termination will be documented in a memo or follow up letter to 
the Principal Investigator. 
 
8.10.2. Recording of Data and Retention of Documents 
Participant data recorded on eCRFs during the study will be documented in an anonymous 
fashion. The participant will only be identified by the participant number. If, as an 
exception, it is necessary for safety or regulatory reasons to identify the participant, the 
Sponsor or its representatives, and the Investigator are bound to keep this information 
confidential. 
The Investigator must retain essential documents for at least two years after the approval of 
the device and for as long as it is required in the UK in compliance with the Data protection 
regulations. Investigator agrees to adhere to the document retention procedures when 
signing the Protocol Investigator’s Signature page. 

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9. 
ADVERSE EVENTS  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding) symptom, or disease temporally associated with the use of a product but not necessarily 
related to the product. An AE may also be called a complication. The capture of AEs will begin 
with the participant’s entry into the study. 
9.1. 
ADVERSE EVENT RECORDING 
All AEs spontaneously reported by the participant and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic procedures 
will be recorded on the appropriate pages of the eCRF. Any clinically relevant deterioration in 
clinical finding is considered an AE and must be recorded. When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event. 
9.2. 
ADVERSE EVENT EVALUATION 
The Investigator should evaluate if each AE is serious, related to the study device and anticipated 
using the following definitions. 
A serious adverse event (SAE) is defined as any untoward medical occurrence that: 
 
It results in death (i.e., the AE actually causes or leads to death); 
 
It is life threatening (i.e., the AE places the participant at immediate risk of 
death); 
 
It requires or prolongs inpatient hospitalization. If a participant is hospitalized 
to undergo a medical or surgical procedure as a result of an AE, the event 
responsible for the procedure, not the procedure itself, should be recorded as 
the event.  For example, if a participant is hospitalized to undergo coronary 
bypass surgery, the heart condition that necessitated the bypass should be 
recorded. Hospitalizations for diagnostic or elective surgical procedures or 
hospitalizations required to allow outcome measurement for the study should 
not be recorded as SAEs: 
 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the participant’s ability to conduct normal life 
functions); 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the device; 
 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g. may jeopardize the participant or may require medical/surgical 
intervention to prevent one of the outcomes listed above); 
 
It is considered sight-threatening by the Investigator. 

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9.3. 
RELATIONSHIP OF THE AE TO THE STUDY DEVICE 
Definite 
A clear cut causal relationship with the study device 
and no other possible cause 
Probable 
A causal relationship with the study device is likely 
although alternate etiologies are also possible  
Possible 
A causal relationship with study device is not 
definite, alternate etiologies are also possible 
Not related 
The AE has no causal relationship to study device 
and/or there is evidence of alternative etiology such 
as concurrent medication or illness. 
Not 
applicable 
The participant has not been exposed to the study 
device. 
The AE will be determined to be device related, making it an adverse device effect (ADE), if it is 
identified to have had a definite, probable or possible causal relationship to the device. 
An AE is unanticipated if the nature, severity, or frequency of the event is not consistent with 
either the known or foreseeable risk of AEs associated with the procedures involved in the 
research that are described in (a) the protocol-related documents, such as the EC-approved 
research protocol, user manuals and the current EC-approved informed consent document, and 
(b) other relevant sources of information such as product labeling and package inserts; or the 
expected natural progression of any underlying disease, disorder, or condition of the 
participant(s) experiencing the AE and the participant’s predisposing risk factor profile for the 
AE. 
9.4. 
SERIOUS AND UNANTICIPATED ADVERSE DEVICE  EFFECTS 
A serious and unanticipated adverse device effect is defined as “any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device 
if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan, or any other unanticipated serious problem associated with 
a device that relates to the rights, safety or welfare of subjects.” 
9.5. 
ADVERSE EVENT REPORTING 
All AEs that occur during the course of the study must be reported on the Adverse Event CRF. 
The Investigator must determine the intensity of the event. 
Mild 
Awareness of sign or symptom, but easily tolerated  
Moderate 
Discomfort enough to cause interference with 
normal daily activities  
Severe 
Inability to perform normal daily activities 

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All SAEs and adverse device effects (ADEs) must be reported by the Investigator to Allergan in 
writing within 24 hours from the point in time when the Investigator becomes aware of the event.  
It is the responsibility of the Investigator to promptly notify the Ethics Committee (EC) of all 
SAEs and unanticipated problems, per the ECs reporting requirements.  
Throughout the course of the proposed study, all efforts will be made to remain alert to possible 
adverse experiences or untoward findings. If adverse experiences occur, the first concern will be 
the safety and welfare of the participant. Appropriate medical intervention will be made.   
The Sponsor will immediately conduct an evaluation of any unanticipated adverse device effect. 
If it is determined by the Sponsor to present an unreasonable risk to study participants, all 
investigations or parts of the investigation presenting that risk will be terminated as soon as 
possible. Termination will occur not later than five working days after the Sponsor makes this 
determination, and not later than 15 working days after first receiving notice of the event. The 
Sponsor will not resume an investigation terminated under these conditions without an additional 
EC approval.  
 
Contact information for reporting Serious Adverse Events: 
Sponsor Contact Information for reporting Serious Adverse Events 
Allergan: 
 
 
ADDITIONALLY please send a copy to: 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
9.6. 
 ANTICIPATED ADVERSE EVENTS 
The following is a list of potential AEs associated with the use of the device:  
 
Nasal discomfort or pain 
 
Epistaxis 
 
Excessive sneezing    
 
Nasal irritation, paresthesia or numbness post-stimulation 
 
Nasal infection, abrasion or inflammation 

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 
Skin irritation or hypersensitivity 
 
Headache (e.g., tension, migraine, etc.)  
 
Facial pain 
 
Excessive salivation 
 
Sensation of teeth vibrating 
 
Excessive rhinorrhea 
 
Temporary aggravation of nasal allergies 
 
Allergic reaction to contact materials 
 
The following is a list of potential AEs associated with the testing procedures at Screening: 
 
Ocular discomfort 
 
Moderate or severe conjunctival injection 
 
Clinically significant decrease in visual acuity  
 
Clinically significant increase in corneal or conjunctival epithelial defects 
 
With use of proxytacaine, temporary burning, stinging and conjunctival redness 
of the eyes 
 
With use of proxytacaine, a rare hyperallergic corneal reaction characterized by 
epithelial keratitis, sloughing of epithelium, corneal filaments and iritis 
 
With the Schirmer test, corneal irritation and abrasion  
 
Allergic reaction to contact materials 
10. PREGNANCY 
Women of Childbearing Potential (WOCBP) include any females who have experienced 
menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation or bilateral oophorectomy) or are not postmenopausal at least 12 months since last 
menses. WOCBP will be required to use designated methods of birth control during the course of 
the study. All women who are pregnant, nursing an infant, or planning a pregnancy will be 
excluded from participation.  
If a participant or Investigator suspects that the participant may be pregnant prior to study device 
administration, the study device must be withheld until the results of pregnancy testing are 
available. If pregnancy is confirmed, the participant must not administer the study device and 
must not be enrolled in the study. 

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11. STATISTICAL HYPOTHESIS AND METHODS OF ANALYSES 
11.1. POWER CALCULATION AND DETERMINATION OF SAMPLE SIZE 
Approximately 35 completed participants will be enrolled. This is an exploratory study and no 
formal sample size calculation was performed. The results from this study may be used to 
determine the appropriate time points and power for future studies.  
11.2. STATISTICAL HYPOTHESES AND LEVEL OF SIGNIFI CANCE 
The null hypothesis for each of the exploratory parameters is the difference in the change from 
the pre-application value at each post-application time point between the intranasal (test) and 
extranasal (control) applications are zero. 
The alternative hypothesis for each of the exploratory parameters is the difference in the change 
from the pre-application value at each post-application time point between the intranasal (test) 
and extranasal (control) applications are not zero. 
The hypothesis can be expressed as: 
H0: Δ = 0 
HA: Δ ≠ 0 mm 
where Δ represents the difference between applications for the change from the pre-application 
value and each post-application time point.  Statistical tests will be two-sided and evaluated at 
an α of 0.05. 
11.3. RANDOMIZATION 
Each participant will be treated with the active and control applications. The sequence of the 
applications will be randomly assigned using a computer-generated randomization schedule.  
Participants will be randomly assigned to one of two application sequences: 
A. Intranasal: Extranasal 
B. Extranasal: Intranasal 
11.4. EVALUABILITY OF DATA 
Full Analysis Set Population (FAS): The FAS population will include all participants who 
completed both applications.  
Per protocol population (PP): The PP population is a subset of the FAS population, which did not 
have a major protocol deviation likely to significantly affect the primary outcome of the study. If 
the PP and FAS populations are exactly the same, then additional exploratory analyses on the PP 
population will not be performed.   
Safety Population: The safety population will include all participants that initiated at least one 
application.  

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11.5. GENERAL STATISTICAL CONSIDERATIONS 
Statistical analyses will use a two-tailed test and will be evaluated at an α of 0.05 unless 
otherwise specified. The mean, standard deviation (SD), median, minimum and maximum will 
be presented for continuous variables such as participant age. For categorical variables, such as 
sex, the number for each category, the total number evaluated, and the percentage will be 
presented. 
The study being exploratory no correction for multiplicity will be made to the statistical 
comparisons. 
11.6. PARTICIPANT ACCOUNTABILITY AND MISSING DATA 
Participation in the study will be summarized by presenting the number of participants who were 
enrolled, the number of participants who only completed the first application and the number of 
participants who completed both applications. No imputation for missing values will be 
performed. 
11.7. PARTICIPANT DEMOGRAPHI C AND BASELINE CHARACTERISTICS 
The demographic and baseline characteristics of the study population observed will be presented 
descriptively.   
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 

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12. FINAL CLINICAL STUDY REPOR T 
A final clinical study report will be prepared after completion of the study. 
13. COMPL IANCE WITH GOOD CLINICAL PRACTICE S, ETHICAL CONSIDERATIONS, 
AND ADMINISTRATIVE ISSUES 
13.1. PROTECTION OF HUMAN PARTICIPANTS 
13.1.1. 
Participant Informed Consent 
Informed consent must take place before any study specific procedures are initiated. Signed and 
dated written informed consent must be obtained from each participant and/or from the 
participant’s parent or legal guardian prior to enrollment into the study. 
All ICFs must be approved for use by the sponsor and receive approval/favorable opinion from 
an Ethics Committee (EC) 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 Sponsor and 
 
prior to submission to the governing EC and that it is read, signed and dated by all participants 
subsequently enrolled in the study as well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by 
 and/or study sponsor and provided in 
writing by 
 and/or study Sponsor prior to the consent process. 
13.1.2. 
Ethics Committee (EC) Approval 
This study is to be conducted in accordance with the harmonized EC standard Clinical 
investigation of medical devices for human subjects – Good clinical practice (EN ISO 14155). 
The Investigator must obtain appropriate EC approval before initiating the study and re-approval 
at least annually. 
13.1.3. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, Good Clinical Practices (GCPs), 
including the International Conference on Harmonisation (ICH) Guidelines, and the ethical 
principles that originated with the Declaration of Helsinki. 
13.1.4. 
Participant Confidentiality 
All personal study participant data collected and processed for the purposes of this study should 
be maintained by the Investigator and his/her staff with adequate precautions to ensure that the 
confidentiality of the data is in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of 
 the Sponsor, the EC approving 
this study and the regulatory authorities will be granted direct access to the study participant’s 
original medical and study records for verification of the data and/or clinical trial procedures. 

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Access to this information will be permitted to the aforementioned individuals to the extent 
permitted by law. 
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the study device may ultimately be marketed, but the participant’s 
identity will not be disclosed in these documents. 
13.2. DOCUMENTATION 
Source documents may include a participant’s medical records, hospital charts, clinic charts, the 
Investigator’s study participant files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiographs. The Investigator’s copy of the CRFs serves as the 
Investigator’s record of a participant’s study-related data. 
13.2.1. 
Retention of Documentation 
All study related correspondence, participant records, consent forms, record of the distribution 
and use of all study device and copies of CRFs should be maintained on file for at least two 
years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region; or until at least two 
years have elapsed since the formal discontinuation of clinical development of the study 
device. 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.  On site and off site storage facilities are allocated which ensure that all stored 
records are identifiable and retrievable, and the storage areas are free from damp and other 
agents which could cause premature deterioration.  All records are retained for the minimum 
legal requirements.  For clinical records the minimum requirement is of 7 years; requirements 
vary for records relative to the execution of individual customer contracts. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address 
of the new custodian. 
13.3. 
REGULATORY STATUS 
The Allergan TrueTear device received CE Mark on December 22, 2014 (CE 615662). It has 
been approved for marketing in Canada and Australia as well. This device has been granted 
marketing authorization by the US Food and Drug Administration (FDA). 
13.4. LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, AND RETURN OR 
DISPO SAL OF STUDY DEVICE 
All devices will be stored and maintained in accordance with the corresponding Instructions for 
Use. Used disposable devices should be discarded after use; unused disposable devices should be 
returned to the Sponsor at the conclusion of the study. A device accountability log will be 
maintained by the site and will be filed in the Trial Master File. 

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13.5. RECORDING OF DATA ON SOURCE DOCUMENTS AND CASE REPORT FORMS (ECRF S) 
The EDC system, EntryPoint i4 is CFR21 Part 11 compliant; all participant data will be captured 
in the participant eCRFs (i.e. source document). The Investigator is responsible for ensuring that 
study data is completely and accurately recorded on each participant’s eCRF and all study-
related materials. EntryPoint i4 has a full data audit trail and access to the eCRF is password 
controlled for individual user accounts; the combined procedures ensure that all changes are time 
stamps and the individual who made the change identified. 
13.6. AMENDMENTS TO THE PROTOCOL 
Any amendment containing major modifications (particularly if it may involve an increased risk 
to the participants) must be approved by the EC before it may be implemented. No change in the 
conduct of the study can be instituted without written approval from the Sponsor. 
13.7. PUBLICATIONS 
Information collected during this clinical study concerning TrueTear and results of the data 
obtained are proprietary and strictly confidential. The Sponsor reserves all rights to any such 
information. Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Sponsor will 
have the final decision regarding the manuscript and publication. 
 

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14. REFERENCES 
1. DEWS. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee 
of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:93-107. 
2. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to 
treatment recommendations. Cornea 2006;25:900-7. 
3. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye; the interaction 
between the ocular surface and lacrimal glands. Cornea 1998;17:584-9.  
4. Plugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye: a 
twenty-five year review. Cornea 2000;19:644-9. 
5. Beuerman RW, Mitchell A, Pflugfelder SC, Stern ME. The lacrimal functional unit, in 
Pflugfelder SC, Beuerman RW, Stern ME (eds.). Dry eye and ocular surface disorders. 
New York, Marcel Dekkar, 2004. 
6. Stern ME, Gao J, Siemarko KF, et al. The role of the lacrimal functional unit in the 
pathophysiology of dry eye. Exp Eye Res 2004;78:409-6. 
7. Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W. Utility 
assessment among patients with dry eye disease. Ophthalmology 2003;110:1412-9. 
8. AAO. Preferred Practice Patterns: Dry Eye Syndrome. 2008. 
9. DEWS. Management and therapy of dry eye disease: report of the Management and 
Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 
2007;5:163-78. 
10. Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. 
Cornea 1997;16:645-8. 
11. Friedman NJ, Butron K, Robledo N, Loudin J, Baba SN, A C. A nonrandomized, open-
label study to evaluate the effect of nasal stimulation on tear production in subjects with 
dry eye disease. Clinical Ophthalmology 2016;10:795-8. 
12. Allergan, Data on File (OCUN009 and OCUN010 studies) 
13. Shiffman RM, Christianson MD, Jacobsen G, Hirsh JD, Reis, BL.  Reliability and 
Validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000 May; 118(5):615-
621 
 
 
 

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15. APPENDICES 

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15.2. APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT AND 
TECHNIQUES 
15.2.1. 
Visual Acuity Procedures 
LogMAR visual acuity should be assessed using an ETDRS chart. The procedure used will be 
consistent with the recommendations provided for using the ETDRS eye chart. Visual acuity 
should be evaluated at the beginning of each visit in the study (i.e., prior to slit lamp 
examination). Participants should use the most recent correction to attain their best corrected 
distance visual acuity (BCVA); if they forget their spectacles, this prescription can be placed in a 
trial frame. 
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", e.g., 
from Prevent Blindness) wall charts are used, the participant viewing distance should be exactly 
10 feet (or as specified by the manufacturer). 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 should be tested first. For reflectance (wall) charts, the chart should be placed 
frontally and be well illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. The 
participant should attempt to read each letter, line-by-line, left to right, beginning with line 1 at 
the top of the chart. The participant should be told that the chart has letters only, no numbers. If 
the participant reads a number, s/he should be reminded that the chart contains no numbers, and 
the examiner should then request a letter in lieu of the number. The participant should be asked 
to read slowly, so as to achieve the best identification of each letter. S/he is not to proceed to the 
next letter until s/he has given a definite response. 
If the participant changes a response (e.g., 'that was a "C" not an "O"') before s/he has read aloud 
the next letter, then the change must be accepted. If the participant 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 participant says 
s/he cannot read a letter, s/he should be encouraged to guess. If the participant identifies a letter 
as one of two letters, s/he 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 

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missed up to and including the last line read. This total sum represents the logMAR visual acuity 
for that eye. 
Example: Participant 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 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR visual acuity 
= 0.18 
 
Repeat the procedure for the left eye. 
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 participant broke 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 the Screening Visit (Visit 1) should be evaluated by the 
Investigator as a potential AE. 
 
 
 

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15.2.2. 
Slit Lamp Biomicroscopy 
Slit lamp biomicroscopy 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: 
 
Cornea  
 
Conjunctiva  
 
Anterior Chamber 
 
Lid 
 
Sodium fluorescein may be used at Investigator’s discretion only for the post-application slit 
lamp biomicroscopy exam. 
 
15.2.3. 
Intranasal Examination 
The intranasal examination can be completed without topical anesthesia using nasal endoscopy 
or a nasal speculum. If using endoscopy, the endoscope is gently inserted into each of the nares 
and the nasal cavity is carefully inspected. If using a nasal speculum, the speculum is gently 
inserted into each of the nares. A light should be utilized to enhance visualization. The speculum 
is opened to expand the nares and the nasal cavity is carefully inspected.  
The nasal cavity is inspected for gross ulceration, mass lesions, severe septal deviations or 
evidence of prior surgery/cautery. Any other gross abnormalities or irregularities should be 
documented accordingly. 
 
15.2.4. 
Schirmer Test with Topical Anesthesia 
At the Screening Visit, one basal Schirmer test will be performed followed by a Schirmer test 
with cotton swab nasal stimulation. The Schirmer test with topical anesthesia will be used to 
assess tear production using the following steps:   
1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent should be 
instilled in both eyes of the participant. 
2. The participant will be instructed to keep the eyes gently closed for one minute.   
3. After opening the eyes and allowing the eyes to recover for approximately one additional 
minute, excess moisture in the inferior fornix is gently removed with a spear. 
4. Schirmer strips (35 mm x 5 mm size filter paper strip) will be placed in each eye at the 
junction of the middle and lateral thirds of the lower eye lid.  
5. Under ambient light, the participant will be instructed to look forward and to blink normally 
during the course of the test. The test should be performed in a room with no direct air on the 
participant’s face. 
6. The Schirmer strips should remain in place until five minutes have elapsed or both strips 
have reached maximum score. 

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7. After five minutes, strips will be removed from both eyes and the amount of wetting will be 
recorded. The strips should be taped to the CRF.   
 
Schirmer test using cotton swab nasal stimulation   
At the Screening Visit, the Schirmer test should be performed using cotton swab nasal 
stimulation. New anesthetic drops should be instilled following the same procedure specified in 
steps #1 to 3 above. 
   
1. With new strips in place, the examiner should insert cotton swabs in the participant’s two 
nostrils simultaneously and gently probe both nasal middle turbinates for approximately 30 
seconds. After this, the examiner can simply hold the swabs in place, applying gentle 
pressure, and repeat probing intermittently as necessary.   
2. Alternatively, the participant can be instructed to hold the cotton swabs and gently probe 
both nasal turbinates simultaneously, resting intermittently before probing again.  The 
examiner should continuously coach the participant on how to perform this test properly.  
3. The Schirmer strips should remain in place until five minutes have elapsed or both strips 
have reached maximum score. 
   
Both Schirmer scores will be recorded and verified that they meet the inclusion criteria. 
 
15.2.5. 
Dry Eye Questionnaires 
 
Ocular Surface Disease Index© (OSDI©) 
To minimize bias, participants will be asked to complete the OSDI questionnaire 
independently and in private after instructions have been provided by site personnel. 
The OSDI is a 12-item questionnaire generated by the Outcomes Research Group at 
Allergan (Irvine, CA),13 which asks participants to describes the nature and frequency of 
their irritation symptoms.  The participant will answer the 12 questions by circling the 
number that best represents each answer:  4 (all of the time), 3 (most of the time), 2 (half of 
the time), 1 (some of the time), or 0 (none of the time).  The final score for the 
questionnaire is calculated as follows: 
Add subtotals from Sections I, II, and III =  A 
Determine total number of questions answered from Sections I, II, and III (do not include 
N/A) = B 
Final OSDI score = A x 25 divided by B   
 
    An example of the questionnaire is as follows: 

Clinical Trial Protocol: OCUN-020 
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Clinical Trial Protocol: OCUN-020 
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Clinical Trial Protocol: OCUN-020 
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Clinical Trial Protocol: OCUN-020 
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15.4. APPENDIX 4: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
Randomized, Controlled, Single-Center, Cross-Over Clinical Study to 
Evaluate Tear Characteristics Following Acute TrueTear™ Use 
Protocol Number: 
OCUN-020 
 
 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. I agree to maintain all 
information supplied by the sponsor in confidence and, when this information is submitted to an 
Ethics Committee (EC) 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: