Randomized, Double-arm, Controlled Clinical Trial to Evaluate the Symptoms in Symptomatic Contact Lens Wearers Following Application of Intranasal Tear Neurostimulator Versus Control (CORIANDER)
Phase: NA
Conditions: Dry Eye Syndromes
Sponsor: Allergan

NCT03325673 
 
Study ID: OCUN-024 
 
Title: Clinical Trial to Evaluate the Symptoms in Symptomatic Contact Lens Wearers Following 
Application of Intranasal Tear Neurostimulator Versus Control 
 
Protocol Date: 26‐Mar‐2018 

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CORIANDER Protocol (OCUN-024)  26mar2018 
2 
Study Personnel 
 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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DOCUMENT CHANGE HISTORY 
 
Revision # 
Originator 
Description of change(s) 
Date 
0.0 
 
Original protocol 
19may2017 
1.0 
 
Included edits from sponsor 
13jun2017 
2.0 
 
Final sponsor edits 
22jun2017 
3.0 
 
Amended to remove groups 
26mar2018 
 
 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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Table of contents 
Document change history ............................................................................................................ 3 
1 
Introduction .......................................................................................................................... 9 
2 
Objectives .......................................................................................................................... 10 
3 
Hypothesis ......................................................................................................................... 10 
4 
Materials and methods ...................................................................................................... 10 
4.1 
Study design ............................................................................................................... 10 
4.1.1 
Overall design ...................................................................................................... 10 
4.1.2 
TrueTear Description............................................................................................ 11 
4.1.3 
Truetear sham control .......................................................................................... 13 
4.1.4 
Randomization ..................................................................................................... 14 
4.1.5 
Masking................................................................................................................ 14 
4.2 
Study population ......................................................................................................... 14 
4.2.1 
Sample size calculation ........................................................................................ 14 
4.2.2 
Number of participants ......................................................................................... 15 
4.2.3 
Inclusion and exclusion criteria ............................................................................. 15 
4.2.4 
Repeated screenings ........................................................................................... 17 
4.3 
Study materials ........................................................................................................... 17 
4.3.1 
Lenses ................................................................................................................. 17 
4.3.2 
Lens care system ................................................................................................. 18 
4.3.3 
Device (TrueTear and TrueTear sham control)..................................................... 18 
4.3.4 
Artificial tears and rewetting drops........................................................................ 18 
4.3.5 
Ordering consumables ......................................................................................... 18 
4.3.6 
Contact lens / lens care Product accountability .................................................... 18 
4.4 
Scheduled and unscheduled visits .............................................................................. 19 
4.4.1 
Screening ............................................................................................................. 19 

CORIANDER Protocol (OCUN-024)  26mar2018 
5 
 
 
4.4.3 
Unscheduled visits ............................................................................................... 21 
4.5 
Study procedures ........................................................................................................ 21 
4.5.1 
Case history ......................................................................................................... 23 
4.5.2 
Determination of symptoms .................................................................................. 23 
4.5.3 
Visual Acuity ........................................................................................................ 23 
4.5.4 
Baseline Ocular Measures ................................................................................... 24 
4.5.5 
Contact Lens Assessment .................................................................................... 24 
4.5.6 
Three-Minute basal Schirmer Test with Topical Anesthesia ................................. 24 
4.5.7 
Determination of refraction ................................................................................... 25 
4.5.8 
Biomicroscopy / Ocular Health evaluation ............................................................ 25 
4.5.9 
Comfort ratings..................................................................................................... 26 
4.5.10 
Assessment of Compliance .................................................................................. 26 
4.6 
Non-standard optometric procedures: ......................................................................... 26 
4.6.1 
Intranasal Examination ......................................................................................... 26 
4.6.2 
Three-minute Schirmer test with cotton swab nasal stimulation ............................ 26 
5 
Participant Training, Dispensing and Home Use of TrueTear ............................................ 27 
6 
Participant training, dispensing and home use of TrueTear sham control .......................... 28 
7 
Monitoring protocol adherence .......................................................................................... 29 
8 
Potential Risks and Benefits to Human participants ........................................................... 29 
9 
Adverse events .................................................................................................................. 29 
9.1 
Adverse Event Recording ............................................................................................ 29 
9.2 
Adverse event evaluation ............................................................................................ 30 
9.2.1 
Severity/Intensity .................................................................................................. 30 
9.2.2 
Relationship to the Study Device .......................................................................... 31 
9.2.3 
Anticipated Adverse Events.................................................................................. 31 

CORIANDER Protocol (OCUN-024)  26mar2018 
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9.3 
Adverse Event Reporting ............................................................................................ 32 
10 
Discontinuation from the study ........................................................................................... 33 
11 
Study completion and remuneration .................................................................................. 34 
12 
Statistical analysis and data management ......................................................................... 35 
12.1 
Statistical analysis ................................................................................................... 35 
12.2 
Data management ................................................................................................... 37 
12.3 
Comments on source documents ............................................................................ 37 
13 
Protocol training ................................................................................................................. 37 
14 
Study monitoring ................................................................................................................ 38 
15 
Study management............................................................................................................ 38 
15.1 
Statement of compliance ......................................................................................... 38 
15.2 
Ethics review ........................................................................................................... 38 
15.3 
Protocol deviations .................................................................................................. 39 
15.3.1 
Major protocol deviations ..................................................................................... 39 
15.3.2 
Minor protocol deviations ..................................................................................... 39 
15.3.3 
Reporting and documenting protocol deviations ................................................... 40 
15.4 
Premature termination of the study .......................................................................... 40 
15.5 
Study participant records ......................................................................................... 40 
15.6 
Retention of study records and data ........................................................................ 40 
16 
Report................................................................................................................................ 40 
17 
References ........................................................................................................................ 41 
 
 
 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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 Confidentiality 
This is a private document and the property of Allergan, Plc. It is therefore confidential to the 
recipient and must not be quoted from or distributed beyond the company to which it is sent 
without the express written permission of Allergan, Plc. Release of information from this 
document is governed by the research agreement on file. 
 
 
 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
8 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ADE 
Adverse device effect 
CI 
Confidence interval 
CCLR 
Centre for Contact Lens Research 
CL 
Contact lens 
CLD 
Contact lens dryness 
CREC 
Clinical Research Ethics Committee 
CRF 
Case report form 
CWT 
Comfortable wear time 
DD 
Daily disposible 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
HCVA 
High contrast visual acuity 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
LLT 
Lipid layer thickness 
logMAR 
Logarithm of the minimum angle of resolution 
MGD 
Meibomian gland disease 
Mm 
Millimeter 
NITBUT 
non-invasive tear break-up time 
NSR 
Non-significant risk 
OTC 
Over-the-counter 
PP 
Per protocol 
SAE 
Serious adverse event 
SD 
Standard deviation 
SiHy 
Silicone hydrogel 
TFOS 
Tear Film and Ocular Surface Society 
TMH 
Tear meniscus height 
US 
United States 
WOCBP 
Women of childbearing potential 
WT 
Wear time 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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1 
INTRODUCTION 
The worldwide contact lens (CL) market in 2016 was estimated to be $7.2 billion dollars in value.1 
Yet drop out from CL wear continues to be one of the major reasons for slow overall growth of this 
market with the most commonly cited reasons for drop out as ‘discomfort and dryness’.2,3 
In 2013, the Tear Film and Ocular Surface Society (TFOS) defined CL dryness (CLD) as: ‘a 
condition characterized by episodic or persistent adverse ocular sensations related to CL wear, 
either with or without visual disturbance, resulting from reduced compatibility between the contact 
lens and the ocular environment, which can lead to decreased wearing time and discontinuation 
of lens wear.’4  
Given the progression of CLD from ‘struggling with symptoms of discomfort’, to ‘reduced wear 
time’ and finally ‘discontinuation of CL wear’, it is important for practitioners to have access to 
appropriate management strategies. CLD is multifactorial and some strategies involve CL-related 
modifiable factors such as material or wear modality.4 Other areas of management address 
patient-related factors such as low tear volume or poor tear quality. Some studies have 
demonstrated reduction in dryness symptoms and increase in CL wear times via either 
intracanalicular5 or inferior punctal occlusion.6 These methods essentially increase the volume of 
tears in the eye. An alternative approach to increasing tear volume would be to stimulate tear 
production. The TrueTear device has been shown to do this.7,8 
Rationale for TrueTear (Intranasal Neurostimulator Device) 
The nasolacrimal reflex is a well-established pathway by which nasal stimuli promote both resting 
basal and bolus tear secretion.9,10  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.11,12  
Reflex activation of the lacrimal glands is also one of the body’s primary compensatory 
mechanisms for addressing ocular surface dryness.13-17 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 TrueTear application results in a 
statistically significant increase in tear production measured by the Schirmer test7,8 and as such 
may provide a novel option for relief of CLD. This study is focused on quantifying the change in 
both comfortable wear time and total wear time following use of TrueTear for 30 days compared 
to a group using TrueTear sham control.   

CORIANDER Protocol (OCUN-024)  26mar2018 
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2 
OBJECTIVES 
The objective of this study is to evaluate the increase in comfort and comfortable CL wear time 
associated with application of TrueTear (active intranasal neurostimulation) compared with 
application of TrueTear sham control (intranasal application which is not electrically active) in 
symptomatic CL wearers. 
The primary outcome variables for this study are:  
 - Contact Lens Dry Eye Questionnaire (CLDEQ-8) 
 - comfort ratings 
 - comfortable wear time (CWT)  
 - total wear time (total WT) 
3 
HYPOTHESIS 
Improvements in CWT and comfort ratings in participants using TrueTear (active device) will be 
superior to those participants using the TrueTear sham control. 
4 
MATERIALS AND METHODS 
4.1 STUDY DESIGN 
4.1.1 OVERALL DESIGN 
This is a prospective, double-masked, controlled, randomized by device (TrueTear vs TrueTear 
sham control), parallel arm study, with up to 6 study visits including a screening visit. Study 
participants (n=80) will be habitual, symptomatic wearers of daily disposable (DD) or reusable 
hydrogel and silicone hydrogel (SiHy) CLs. Symptomatic participants will be recruited, with a 
minimum average wear of 2 days/week and ≥3 hours of wear/day. It is expected that the majority 
of symptomatic wearers will be wearing the lenses on average 4-7 days/week. Wearers will be 
randomized to use the active device or the intranasal sham control.  
 
 
Visit schedule:  
There will be up to 6 study visits and cumulative total time commitment for the study is 
approximately 6 hours. 
 Permitted time interval between 
V1 and V2 is 7- 45 days. 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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4.1.2 TRUETEAR DESCRIPTION 
The TrueTear device delivers small electrical currents to the inner cavity of the nose, activating 
nerves that stimulate the body’s natural tear production. The device is approved in Canada to 
increase tear production during stimulation. Use of the product to relieve CLD is investigational. 
The device consists of four distinct parts (Figure 3): 
1. 
A reusable Base Unit which produces the electrical stimulation waveform. 

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CORIANDER Protocol (OCUN-024)  26mar2018 
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of illuminated LEDs on the Base Unit. The device internally records the time and duration of device 
use. 
4.1.2.2 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. 
4.1.2.3 COVER 
The Cover may be placed over the top of the Tip attached to the Base Unit for protection in 
between uses. 
4.1.2.4 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. 
4.1.3 TRUETEAR SHAM CONTROL  
The comparator arm in this study is the TrueTear sham device, which is not electrically active, and 
will be applied intranasally. The sham device (Figure 4) consists of a Base Unit and Tip Assembly 
that have been modified so that the depth to which the probes are inserted into the nose is limited.  
All other parts of the device are identical. This sham device is also electrically nonfunctional; the 
device powers on, but no electrical stimulation energy is delivered through the Tip Assembly. 
Participants are to be instructed to place only the tips of the device into both nostrils 
simultaneously so that the nose stop on the device touches the participant’s septum. 

CORIANDER Protocol (OCUN-024)  26mar2018 
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Figure 4:  TrueTear Sham Control Base Unit with Disposable Tips 
4.1.4 RANDOMIZATION 
A 
randomization 
schedule 
will 
be 
generated 
using 
a 
web-based 
program: 
(www.randomization.com) with stratification by groups based on frequency of lens wear during 
the week. The final study randomization schedule will be generated 
 
 and provided to the research assistants for the study. Study investigators will 
remain masked to the randomization schedule until the study is completed and the database is 
locked.  
4.1.5 MASKING 
The study will be double-masked with both participant and site personnel interacting with the 
participant being masked. The participants will be aware that they will be randomized to an 
intranasal device with only one being electrically active. Neither participant or site personnel 
interacting with the participant will be told which device the participant is randomized too.  
Researchers tasked with collecting study data will be masked throughout the study. The initial use 
of TrueTear or TrueTear sham control in V2-1 and reviewing the procedure for proper use of the 
device in V2-1, V2-2 and V3 will be conducted by either research assistants, unmasked 
investigators or study sponsor representatives.  
 
4.2 STUDY POPULATION 
4.2.1 SAMPLE SIZE CALCULATION 
Due to the exploratory nature of this study, the planned sample size was determined empirically.   

CORIANDER Protocol (OCUN-024)  26mar2018 
15 
4.2.2 NUMBER OF PARTICIPANTS 
 
 Up to 120 eligible participants will be dispensed / randomized with study 
products, with a target of 80 completing the study. Informed consent will be obtained for all 
participants prior to their enrolment in the study.  
 
4.2.3 INCLUSION AND EXCLUSION CRITERIA 
A person is eligible for inclusion in the study if he/she: 
 
 
 
 
 
 
 
 
4. In at least one eye, has a cotton swab nasal stimulation Schirmer test score at least 4 mm 
greater than 3 minute Schirmer with anesthesia basal score in the same eye at the 
Screening Visit  
5. Is an adapted soft contact lens wearer and currently wears lenses an average of at least 
2 days per week, with an average minimum wearing time of 3 hours each day over the 
past month, AND is able and willing to wear lenses for at least 6 hours on four study day 
visits. 
 
 
 
7. Has at least 20/40 visual acuity in both eyes with CL correction 
8. Is symptomatic using Young’s categorization as outlined in this protocol. 
 
 
 
 
A person will be excluded from the study if he/she: 
 
 
 
 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
9. Has undergone refractive error surgery; 
 
 
 
12. 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; 
13. Have had nasal or sinus surgery (including history of application of nasal cautery) or 
significant trauma to these areas;  
 
 
 
 
 
 
 
  
 
  
15. Have a vascularized polyp, severely deviated septum or severe nasal airway obstruction 
as confirmed by intranasal examination performed at the Screening Visit; 
16. Have an active implanted metallic or active implanted electronic device in the head, a 
cardiac demand pacemaker, or an implanted defibrillator. 

CORIANDER Protocol (OCUN-024)  26mar2018 
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4.2.4 REPEATED SCREENINGS 
In some circumstances a repeated screening may need to be scheduled. Examples include, but 
are not limited to: 
1. Incomplete information available at time of screening to determine eligibility (e.g. current 
lens brands worn, history from current eye care practitioner, etc.) 
2. Study procedures unable to be completed in time scheduled for visit; 
3. Study products not available at the time of the screening visit; 
4. A transient health condition which may affect the eye(s) (e.g. a common cold, active 
allergies, fatigue, etc.) 
5. Seven days after the final use of short term medications (e.g. antibiotics, antihistamines, 
etc.) 
6. Reassessment of baseline ocular conditions (e.g. corneal and/or conjunctival staining, 
scars, etc.) 
The maximum total number of repeated screenings permitted will be 1. 
 
4.3 STUDY MATERIALS 
4.3.1 LENSES 
The participant will continue with their habitual CLs throughout the study. A one month supply of 
their current lenses will be dispensed to the participant at V2-1. 
The participant must bring an unopened package of their current CLs to the screening visit. The 
specification of the CLs will be noted, and a one month supply of the lenses ordered by the CCLR. 
The CLs must be commercially available in Canada. 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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4.3.2 LENS CARE SYSTEM 
A lens care system will be used when a participant habitually wears anything other than soft daily 
disposable CLs. They will continue with their habitual lens care system throughout the study. A 
one month supply of their lens care system will be dispensed to the participant at V2-1. 
The participant must bring their lens care system with them to the screening visit. The type of 
system will be noted, and a one month supply ordered by the CCLR. The lens care system must 
be commercially available in Canada. 
4.3.3 DEVICE (TRUETEAR AND TRUETEAR SHAM CONTROL) 
Either a TrueTear or TrueTear sham control device will be dispensed at V2-1 along with a supply 
of tips. A second supply of tips will be dispensed at V4. Additional tips may be dispensed as 
required to allow participant access to a new tip every 24 hours as per usage guidelines. This may 
be required if the participant is seen at the end of each visit window for example.  
4.3.4 ARTIFICIAL TEARS AND REWETTING DROPS 
The use of artificial tears / rewetting drops is not permitted throughout the study. A participant 
must cease use of artificial tears / rewetting drops at least three days prior to visit 2, and must 
commit to not using any of these products throughout the duration of the study period. 
4.3.5 ORDERING CONSUMABLES 
The sponsor will provide TrueTear and TrueTear sham control devices (base units and associated 
tips). The CCLR will order CLs and CL care systems for each participant.  
4.3.6 CONTACT LENS / LENS CARE PRODUCT ACCOUNTABILITY 
Accountability logs will be kept to include the number of lenses and lens care system bottles 
received, dispensed, unused and returned to sponsor (where relevant). All products dispensed to 
participants will be recorded in the study binder. 
4.3.6.1 TRUETEAR AND TRUETEAR SHAM CONTROL ACCOUNTABILITY 
Each Base Unit of TrueTear and TrueTear sham control devices have 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 (for either TrueTear 

CORIANDER Protocol (OCUN-024)  26mar2018 
19 
or TrueTear sham control), is provided in an air tight sealed pouch, which is labelled with the lot 
number and expiration date. The lot number of the Tips 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. 
 
4.4 SCHEDULED AND UNSCHEDULED VISITS 
This study has a total of 6 study visits, including the screening visit. 
4.4.1 SCREENING  
The investigator will determine participant eligibility using the inclusion and exclusion criteria.  

CORIANDER Protocol (OCUN-024)  26mar2018 
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CORIANDER Protocol (OCUN-024)  26mar2018 
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4.4.3 UNSCHEDULED VISITS 
An unscheduled visit is defined as an interim visit requested by the participant or investigator due 
to an unanticipated problem. Data recorded at these visits will be entered into the database. Only 
relevant and applicable unscheduled visit information will be included in the final report as deemed 
necessary by the lead investigator.  
 
4.5 STUDY PROCEDURES 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
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CORIANDER Protocol (OCUN-024)  26mar2018 
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STANDARD OPTOMETRIC PROCEDURES: 
4.5.1 CASE HISTORY 
Demographic information from the participant will be obtained, including age, gender, CL details, 
artificial tear use, and relevant health and medical information. 
4.5.2 DETERMINATION OF SYMPTOMS 
Patients will be considered symptomatic based on Young’s catergorization.4 This corresponds to 
the dark grey areas in Table 3 below: 
Table 3: Young’s categorization for contact lens dry eye score 
 
4.5.3 VISUAL ACUITY 
Visual acuity will be measured using high contrast computer-generated acuity charts. Participants 
will be asked to read letters that progressively decrease in size on a computer screen located at 
a distance of 6 meters.  
 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
24 
4.5.4 BASELINE OCULAR MEASURES 
4.5.4.1 PRE-LENS NON-INVASIVE TEAR BREAK UP TIME 
Pre-lens non-invasive tear breakup time (NITBUT) will be assessed using a placido-disc device. 
The rings of the disc will be projected onto the tear film and the time to first disruption of that image 
in between blinks will be noted. An average result will be calculated from three measures in each 
eye. 
4.5.4.2 TEAR MENISCUS HEIGHT (TMH) 
An image of the tear meniscus in both eyes will be taken using the Oculus Keratograph 5M 
instrument. TMH will be calculated as an average of two measures taken using the on-screen 
calipers. 
4.5.5 CONTACT LENS ASSESSMENT 
Contact lens wettability and deposition will be graded using a 0-4 scale (0.25 steps),  
0 = excellent, 4 = poor 
 
4.5.6  THREE-MINUTE BASAL SCHIRMER TEST WITH TOPICAL ANESTHESIA 
At the Screening Visit, one basal Schirmer test with anesthesia will be performed followed by a 
Schirmer test with cotton swab nasal stimulation. The Schirmer test with topical anesthetic will be 
used to assess tear production using the following steps:   
1. 
One drop of topical anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent 
should be instilled in each eye 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.  

CORIANDER Protocol (OCUN-024)  26mar2018 
25 
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 three minutes have elapsed or both strips 
have reached maximum score. 
7. 
After three minutes, strips will be removed from both eyes and the amount of wetting will be 
recorded. The strips should be taped to the CRF.   
8.  
Following this test, a three-minute Schirmer test with cotton swab nasal stimulation will be 
performed (see Section 4.6.2).  
4.5.7 DETERMINATION OF REFRACTION 
Participants will have a measure of their ocular prescription taken using an autorefractor. A full 
subjective refraction will only be conducted where it is not possible to correct either eye to better 
than 0.20 logMAR with their habitual contact lenses. 
4.5.8 BIOMICROSCOPY / OCULAR HEALTH EVALUATION 
The participant will sit behind a slit lamp and the following will be assessed. 
4.5.8.1 BULBAR AND LIMBAL HYPEREMIA 
The redness of the bulbar and limbal conjunctiva of both eyes will be assessed using the EFRON 
Grading scale (0 to 4, 0 = no redness).  
4.5.8.2 CORNEAL AND CONJUNCTIVAL STAINING  
A sodium fluorescein strip, wetted with a few drops of saline, will be applied to the superior bulbar 
conjunctiva of both eyes. Staining will be graded using the CCLR scale (0 to 100, 0 = no staining) 
while viewing with cobalt blue light through a Wratten no. 12 barrier filter.  
4.5.8.3 PALPEBRAL CONJUNCTIVAL HYPEREMIA AND ROUGHNESS 
The redness and roughness of the upper and lower eyelids (tarsal plate zone 2) will be assessed 
using the CCLR scale (0 to 100, 0 = no redness/roughness). 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
26 
4.5.9  COMFORT RATINGS 
Participants will be asked to complete subjective ratings at the study visits and at home on certain 
study days. They will record their responses on an online database 
 
 Responses will be captured at 
screening, on study day 0 (at V2-1, V2-2), and subsequently at days 3, 6, 8, 12, 15, 18, 21, and 
24 where comfort will be recorded after lens insertion, after 2 hours of lens wear and prior to lens 
removal at the end of the wearing day. Comfort will be assessed on a 100 point scale with a score 
of 0 indicating “Extremely uncomfortable” and a score of 100 indicating “Extremely comfortable.”  
Verbal instructions on how to complete the diary will be provided and email reminders will be send 
to the participant for each rating. The CLDEQ-8 questionnaires will also be completed at Visit 1, 4 
and 5 using the 
 on the participant’s phone.  The individual assessments on the 
CLDEQ-8 questionnaire will be summarized to provide a score of 1 to 37. 
4.5.10 ASSESSMENT OF COMPLIANCE 
Participants will be asked to declare the number of days of contact lens wear and the number of 
times the intranasal device has been used. 
4.6 NON-STANDARD OPTOMETRIC PROCEDURES: 
4.6.1  INTRANASAL EXAMINATION 
The intranasal examination can be completed without topical anesthesia using  a nasal speculum. 
The speculum is gently inserted into the lower end of each of the nares. A light should be utilized 
to enhance visualization. The speculum is opened to expand the nares such that the the nasal 
cavity can be 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.   
4.6.2 THREE-MINUTE 
SCHIRMER 
TEST 
WITH 
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 
in Section 4.5.6 above. 

CORIANDER Protocol (OCUN-024)  26mar2018 
27 
1. 
With new strips in place, the participant should be instructed to hold the cotton swabs and 
gently probe both nasal turbinates simultaneously, resting intermittently before probing again 
if necessary. The examiner should continuously coach the participant on how to perform this 
test properly.   
2. 
The Schirmer strips should remain in place until three minutes have elapsed or both strips 
have reached maximum score or until both eyes have responded with minimal inclusion 
criteria of at least an increase of 4 mm compared to Basal Schirmer Scores.  
Both Schirmer scores will be recorded and verified that they meet the inclusion criteria.   
5 
PARTICIPANT TRAINING, DISPENSING AND HOME USE OF TRUETEAR  
On Day 0, participants randomized to the TrueTear group will be provided a TrueTear device and 
disposable tips to take home with them and use daily. Participants will be instructed to use the 
device as described in the Patient Guide. They will receive training to perform intranasal 
neurostimulation and will receive a copy of the Patient Guide. 
For TrueTear application, participants 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. They will be 
instructed to fully insert the tips of the TrueTear into both nostrils simultaneously towards the top 
and front of the nose (as in Figure 5). 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 instructed to replace the Tips with a new one if they do not feel 
any sensation.   
For the initial in-office device application at Day 0, each participant will be trained on the device 
consistent with instructions in the patient guide. At Day 0 follow up and 1 week, trained clinical 
personnel will review procedures for the proper use of the device (e.g., correct positioning 
intranasally, frequency and duration of use, daily replacement and disposal of tips, etc.) with 
participants.  
 

CORIANDER Protocol (OCUN-024)  26mar2018 
28 
 
Figure 5: Use of the TrueTear: (L) Starting position and (R) Correct application position by inserting  
the disposable tips fully into the nasal cavity and to the front of the nose. 
6 
PARTICIPANT TRAINING, DISPENSING AND HOME USE OF TRUETEAR 
SHAM CONTROL 
On Day 0, participants randomized to the TrueTear sham control group will be provided a 
TrueTear sham control device and disposable tips to take home with them and use daily. 
Participants will be instructed to use the device as described in the Patient Guide. They will receive 
training to perform intranasal neurostimulation and will receive a copy of the Patient Guide. 
For TrueTear sham control application, participants will be instructed to fully insert the tips of the 
sham device into both nostrils.  Participants will be told to apply and control the intensity of 
stimulation by pressing the plus (+) or minus (-) buttons on the device.  When using the device, 
participants will be told the LEDs on the device are illuminated when stimulation is being delivered, 
even if they do not feel a “tickle” sensation.  Participants will be told they can cease stimulation by 
pressing the minus button on the device or by withdrawing the device from the nostrils. 
For the initial in-office device application at Day 0, each participant will be trained on the device, 
consistent with instructions in the patient guide. At Day 0 follow up and 1 week, trained clinical 
personnel will review procedures for the proper use of the device (e.g., correct positioning 
intranasally, frequency and duration of use, daily replacement and disposal of tips, etc.) with 
participants. 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
29 
7 
MONITORING PROTOCOL ADHERENCE 
Guidelines to be included on adherence to visit windows and windows around other data collection 
points (i.e. subjective ratings). Procedures for monitoring and reporting deviations from the 
windows are described in the protocol. 
8 
POTENTIAL RISKS AND BENEFITS TO HUMAN PARTICIPANTS 
This is a non-significant risk (NSR) device study because of the use of marketed products and 
standard optometric assessments. This device has been granted marketing authorization by the 
US Food and Drug Administration (FDA) for the purpose of temporarily increasing tear production 
during stimulation. 
Contact lenses in this study will be worn on a daily wear basis, with the participant continuing with 
their normal lenses and solutions, and with lenses being worn in accordance with their normal 
wear schedule. Adverse events and/ or complications in daily wear of soft contact lenses can 
occur (e.g.: inflammation and infection). When contact lenses are worn on a daily wear basis there 
is a small risk of an adverse event compared to not wearing contact lenses.  
Anticipated risks from use of TrueTear may include: an increase in nasal secretions, 
uncomfortable sensations, epistaxis and other nasal irritations. The full list of potential adverse 
events from the use of the device is detailed in section 9 (Adverse Events) below.  
Anticipated benefits may be a reduction in CL discomfort symptoms and longer comfortable 
wearing time of CLs over the course of the study. 
9 
ADVERSE EVENTS 
See CCLR SOP012 for a description of adverse event definitions, adverse event management 
and reporting. 
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 CRF. Any clinically relevant deterioration in 
clinical finding is considered an AE and should be recorded. When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event. 

CORIANDER Protocol (OCUN-024)  26mar2018 
30 
9.2 ADVERSE EVENT EVALUATION 
The Investigator should evaluate if each AE is serious, related to the applicable 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 investigational 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. 
9.2.1 SEVERITY/INTENSITY   
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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31 
9.2.2 RELATIONSHIP 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. 
9.2.3 ANTICIPATED ADVERSE EVENTS 
The following is a list of potential AEs associated with the use of TrueTear or TrueTear sham 
control:  
• 
Nasal discomfort or pain 
• 
Epistaxis 
• 
Excessive sneezing    
• 
Nasal irritation, paresthesia or numbness post-stimulation 
• 
Nasal infection, abrasion or inflammation 

CORIANDER Protocol (OCUN-024)  26mar2018 
32 
• 
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 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
33 
9.3 ADVERSE EVENT REPORTING 
As per CCLR SOP012, all SAEs (Serious Adverse Events) must be reported by the Investigator 
to Allergan 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.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 DISCONTINUATION FROM THE STUDY 
Participants discontinued from the study will be reimbursed 
 for their active 
involvement in the study (including the initial screening visit).  Participants may be discontinued at 
the discretion of the investigator, sponsor or participant. The following is a list of possible reasons 
for discontinuation from the study: 
• 
Screening failure: Participants will be discontinued if they do not meet the inclusion and 
exclusion criteria outlined in section 4.2.3. 

CORIANDER Protocol (OCUN-024)  26mar2018 
34 
• 
Unacceptable performance with products to be used in study: Participants may be 
discontinued if they are unable to achieve acceptable comfort and /or vision with the study 
products, or if they are unable or unwilling to use the intranasal device as instructed. 
• 
Positive slit lamp finding:  Participants may be permanently discontinued from the study 
depending on the severity of the condition and on the judgement of the investigator.   
• 
Adverse event: If a participant experiences an adverse event during the study, they may 
be discontinued based on the clinical judgement of the investigator or at the participant’s 
request. 
• 
Symptoms: If the participant has persistent symptoms, they may be discontinued based 
on the clinical judgement of the investigator. 
• 
Disinterest, relocation or illness: The participant may choose to discontinue due to reasons 
within or beyond their control. 
• 
Violation of protocol or non-compliance:  The participant will be discontinued if they are 
unable or unwilling to follow the protocol specified visit schedules and/or study procedures. 
• 
Instillation of topical ocular medication:  The participant will be discontinued if they elect / 
are required to use a topical ocular medication during the study.  
• 
A confirmed positive pregnancy test at any time during the study. 
• 
Lost to follow-up:  The participant will be discontinued if they cannot be contacted and do 
not return for a final exit visit, and if the investigator has made a reasonable effort to contact 
the participant for a final study visit. 
• 
Premature termination of the study by the sponsor, the CCLR or the Office of Research 
Ethics at the University of Waterloo. 
A discontinuation form will be completed, which requires the signatures of both the participant and 
the investigator except where the participant is lost to follow-up in which case only the signature 
of the investigator is required.   
11 STUDY COMPLETION AND REMUNERATION 
At the last scheduled protocol visit, a study completion form will be completed, which requires the 
signatures of both the participant and the investigator.  The participants will also be provided with 
a letter of appreciation.    

CORIANDER Protocol (OCUN-024)  26mar2018 
35 
This study involves partial deception which must be explained to the participant at their last study 
visit (or study exit if discontinued earlier). Each participant will receive an information letter at their 
last visit which explains the nature of the partial deception and why the study had to be designed 
in such a way. Each participant will be given time to read, understand and ask questions.  
Once their involvement in the study is complete, participants will be informed about receiving 
feedback following study completion in the Letter of Appreciation. 
 
 
12 STATISTICAL ANALYSIS AND DATA MANAGEMENT 
12.1 STATISTICAL ANALYSIS 
 
 Descriptive statistics will be provided on information 
regarding baseline variables (age, gender, refractive error distribution, etc.).  
Approximately 80 participants will be enrolled and randomized. 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.  
Analysis of variables will be conducted separately on each eye, and data will not be pooled. The 
study eye will be defined as the qualified eye with the greatest increase in tear production with 
stimulation by a cotton swab at the Screening Visit (V1). If both eyes qualify and have the same 
increase in tear production with stimulation by a cotton swab, then the right eye will be designated 
as the study eye. Table 4 lists the exploratory outcome variables and anticipated statistical 
procedures. 

CORIANDER Protocol (OCUN-024)  26mar2018 
36 
Table 4: Statistical procedures 
Variable 
Analysis 
Statistical test 
Contact Lens Dry Eye 
Questionnaire-8 
(CLDEQ-8), 
Comfort (scored 
immediately after 
insertion, after 2 hours 
and immediately before 
lens removal), 
Comfortable wear time 
and Total wear time 
Descriptive statistics 
Mean, Standard Deviation, Min, Max, Count by 
visit 
Effect of application by visit 
(comparison of change from 
baseline between application 
groups) 
t-test / Wilcoxon rank-sum test (as appropriate) 
Stratified analyses by visit 
(comparison of change from 
baseline between application 
groups stratified by CL freq strata 
and CL type) 
t-test / Wilcoxon rank-sum test (as appropriate) 
Pre-lens non-invasive 
tear breakup time 
(NITBUT) and Tear 
meniscus height (TMH) 
Descriptive statistics 
Mean, Standard Deviation, Min, Max, Count by 
visit 
Effect of application by visit 
(comparison of change from 
baseline between application 
groups) 
t-test / Wilcoxon -rank-sum test (as appropriate) 
 
All data will be tested for normality of distribution using Shapiro-Wilk tests.  The appropriate test 
will be selected based on tests of normality.  
The critical alpha level for statistical significance will be set at p  0.05, with no adjustments for 
multiple comparisons.  All participants who were evaluated will be used in the analysis. In the 
event of missing data, individual data points will be excluded in the analysis and not extrapolated 
from the collected data. As this is a proof of concept, additional statistical analysis may be 
conducted. 
Dependent on the outcome of the study, analysis may be conducted on the contact lenses that 
have been collected. If the decision is made to not analyse the contact lenses then they will be 
destroyed according to University guidelines.  
Additional analyses may be performed to examine the results observed relative to the device 
usage recorded by the device itself. 
Safety assessments include adverse events, visual acuity and slit lamp biomicroscopy.  
Summaries by application will be prepared of the number and percentage of subjects reporting 
one or more adverse events, the number and percentage of subjects reporting one or more device-

CORIANDER Protocol (OCUN-024)  26mar2018 
37 
related adverse events, the number and percentage of eyes with a clinically significant change in 
visual acuity at each follow-up exam and the number and percentage of eyes with a clinically 
significant change in slit lamp biomicroscopy at each visit.  A clinically significant change in visual 
acuity is defined as a change of more than 2 lines (logMAR score change greater than 0.2).  A 
clinically significant change in the slit lamp biomicroscopy parameters will be a change of 2 or 
more grades. 
12.2 DATA MANAGEMENT 
Data from this study will be retained by the CCLR for a minimum of 25 years on a password-
protected server. After 25 years, data will be disposed of in accordance with the guidelines laid 
out by the University of Waterloo.  
At the completion of the study the CCLR will provide a copy of the study data to the sponsor when 
requested. Data will typically be sent using a secure file share system operated by the University 
of Waterloo called 
 which uses 128bit (or 256bit) SSL encryption.  This system provides a 
secure way to transfer files when email is not appropriate, whether because of file size, file type 
or concerns over security.
 includes features such as password protection, a restricted time 
period for download, IP logging and email notification of download. Files may be encrypted prior 
to transmission at the request of the sponsor. Using this method means that data files are only 
stored on University of Waterloo servers.  
12.3 COMMENTS ON SOURCE DOCUMENTS 
Data analysis will not be conducted on comments which have been recorded in the source 
documents. Only highlighted comments will be entered into the study database. Only relevant and 
applicable comments will be included in the final report as deemed necessary by the lead 
investigator.  
13 PROTOCOL TRAINING 
All study personnel will be required to complete training prior to their involvement in the study. A 
series of training modules will be developed for the study and records of training will be kept at 
the CCLR. 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
38 
14 STUDY MONITORING 
Status reports will be provided to the study sponsor by email on a regular basis.  
Status reports will include: 
• 
The number of participants screened, enrolled, and randomized (i.e. assigned a study ID 
number), discontinued and completed. 
• 
Details of protocol deviations. 
• 
Reports of unintended events.  
Study monitoring visits may be conducted throughout the study and will be scheduled by the study 
sponsor in conjunction with the lead investigator. In addition study records may be inspected at 
the CCLR by the sponsor, the sponsor's designate, the Office of Research Ethics at the University 
of Waterloo, and by regulatory authorities in Canada and the United States, namely Health 
Canada and the United States Food and Drug Administration (FDA); however, no records 
containing identifiable/personal information will be permitted to leave the custody of the CCLR. 
15 STUDY MANAGEMENT 
15.1 STATEMENT OF COMPLIANCE 
This clinical study is designed to be in compliance with the ethical principles in the Declaration of 
Helsinki, with the ICH guidelines for Good Clinical Practice (GCP), GCP principles described in 
ISO 14155, the University of Waterloo’s Guidelines for Research with Human Participants and 
with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, 2nd Edition. 
• 
Declaration of Helsinki 
• 
ICH E6 - International Conference on Harmonisation; Good Clinical Practice 
• 
ISO 14155 Clinical investigation of medical devices for human subjects – Good clinical 
practice 
• 
http://iris.uwaterloo.ca/ethics/human/guidelines/index.htm 
• 
http://iris.uwaterloo.ca/ethics/human/ethicsReview/UWStatement.htm 
• 
http://www.pre.ethics.gc.ca/eng/policy-politique/initiatives/tcps2-eptc2/Default/ 
15.2 ETHICS REVIEW 
This protocol will be submitted to and reviewed through the Office of Research Ethics (ORE) at 
the University of Waterloo. Notification of ethics clearance of the application is required prior to 
the commencement of the study. 

CORIANDER Protocol (OCUN-024)  26mar2018 
39 
15.3 PROTOCOL DEVIATIONS 
Protocol deviations are unanticipated or unintentional changes to a study after it has received prior 
sponsor approval and ethics clearance. Protocol deviations can be major or minor.  
15.3.1 MAJOR PROTOCOL DEVIATIONS 
Major protocol deviations may impact the research protocol, information consent document or 
other study materials, usually cannot be anticipated ahead of time and are often necessary to 
ensure the safety and welfare of the participants. 
The following are examples of protocol deviations that must be reported to the ORE: 
• 
Changes in procedures initiated to eliminate immediate risks/hazards to participants; 
• 
Enrollment of participants outside the protocol inclusion/exclusion criteria whether agreed 
to or not by the sponsor; 
• 
Medication / device / intervention errors (i.e. incorrect device / incorrect contact lens(es) 
dispensed / incorrect care system dispensed); 
• 
Inadvertent deviation in specific research intervention procedures or timing of the research 
intervention which could impact upon the safety or efficacy of the study-related intervention 
or upon the experimental design; 
• 
Information consent documentation violations: no documentation of informed consent; 
incorrect version of, or incomplete, informed consent documentation used. 
15.3.2 MINOR PROTOCOL DEVIATIONS 
Protocol deviations caused by or which originate with research participants are considered minor, 
and normally are not reported to the ORE unless they result in increased risk to the participant(s). 
The following are examples of protocol deviations that are considered minor and do not require 
reporting to the ORE: 
• 
Logistical or administrative aspects of the study (e.g., study participant missed 
appointment, change in appointment date); 
• 
Inadvertent deviation in specific research intervention procedures or timing of the research 
intervention which would not impact upon the safety or efficacy of the study-related 
intervention or upon the experimental design (i.e., missing a measurement during a 
session that is not considered critical for the study).  

CORIANDER Protocol (OCUN-024)  26mar2018 
40 
15.3.3 REPORTING AND DOCUMENTING PROTOCOL DEVIATIONS 
Major protocol deviations must be reported to the ORE within 7 days of the deviation occurring (or 
its discovery) using the Protocol Deviation Report Form 107 (PDRF).  Information from the PDRF 
is provided to the Clinical Research Ethics Committee (CREC) at the next monthly meeting. 
All protocol deviations (major and minor) occurring during the study will be documented and 
included in the final report. 
15.4 PREMATURE TERMINATION OF THE STUDY 
The sponsor, the CCLR or the Office of Research Ethics at the University of Waterloo may 
terminate the study at any time for any reason. 
15.5 STUDY PARTICIPANT RECORDS 
Study participant records will be completed to comply with GCP guidelines. Records will contain: 
• 
Unique study acronym and/or code; 
• 
Participant ID; 
• 
Date enrolled; 
• 
Confirmation by lead investigator that participant met eligibility criteria; 
• 
Confirmation that participant received a signed and dated copy of informed consent; 
• 
Exit date; 
• 
Lead investigators signature confirming study exit. 
15.6 RETENTION OF STUDY RECORDS AND DATA 
Records and data from this study will be retained for a minimum of 25 years. Details regarding 
storage procedures are given in CCLR SOP 6.3.  
16 REPORT 
A report will be sent to the sponsor according to terms described in the study contract. 
 
 

CORIANDER Protocol (OCUN-024)  26mar2018 
41 
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Young G, Veys J, Pritchard N, Coleman S. A multi-centre study of lapsed contact lens 
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Nichols KK, Redfern RL, Jacob JT, et al. The TFOS International Workshop on Contact 
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Zilstorff-Pedersen K. Quantitative Measurements of the Nasolacrimal Reflex. Archives of 
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Philip G, Baroody FM, Proud D, Naclerio RM, Togias AG. The human nasal response to 
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Holtzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin 
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Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. 
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Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic keratitis. 
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Tsubota K. The importance of the Schirmer test with nasal stimulation. American journal 
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corneas. Investigative ophthalmology & visual science. Apr 2000;41(5):1063-1069. 
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Beuerman RW, Schimmelpfennig B. Sensory denervation of the rabbit cornea affects 
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