Goblet Cell Degranulation Produced by Nasal Neurostimulation: A Randomized, Controlled Study in Patients With Dry Eye Disease
Phase: NA
Conditions: Dry Eye Syndromes
Sponsor: Allergan

 
   
 
 
 
         NCT 03827564 
 
Study ID: 1919-802-019 
 
 
Title: Goblet Cell Degranulation Produced by Nasal Neurostimulation: A 
Randomized, Controlled Study in Patients with Dry Eye Disease 
 
                                  Protocol Date: MARCH 4, 2019 

 
 
Approval Date: 
 
04-Mar-2019
 
 
Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
 
1 
Title Page 
Protocol Title: Goblet Cell Degranulation Produced by Nasal Neurostimulation: A Randomized, 
Controlled Study in Patients with Dry Eye Disease 
Protocol Number: 1919-802-019 
Product: Intranasal Tear Neurostimulator (ITN) [TrueTear®] 
Brief Protocol Title: Goblet Cell Degranulation Produced by ITN in DED 
Development Phase: Post-Market 
Sponsor Name: Allergan, Inc. 
Legal Registered Address: 
2525 Dupont Drive, Irvine, CA 92612, USA 
Manufacturer: Allergan 
Regulatory Agency Identifying Number: NCT to be added (in progress) 
Serious Adverse Event Reporting: 
Allergan Device Medical Safety Physician Contact Information: 
Allergan Signatory:  
Vice President, Therapeutic Area Head 
Anterior Segment and Consumer Eye Care 
Allergan, Inc. 
Refer to the final page of this protocol for electronic signature and date of approval. 

 
Approval Date: 
 
04-Mar-2019
 
 
Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
 
2 
Table of Contents 
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................2 
List of Tables ..................................................................................................................................4 
List of Figures .................................................................................................................................5 
1. 
Protocol Summary ..........................................................................................................6 
1.1. 
Synopsis ............................................................................................................................6 
1.2. 
Schema ..............................................................................................................................6 
1.3. 
Schedule of Activities .......................................................................................................7 
2. 
Introduction ...................................................................................................................10 
2.1. 
Study Rationale ...............................................................................................................10 
2.2. 
Background .....................................................................................................................10 
2.2.1. 
Device Description ..........................................................................................................11 
2.2.2. 
Extranasal Control Description .......................................................................................13 
2.3. 
Benefit/Risk Assessment ................................................................................................13 
3. 
Objectives and Endpoints ............................................................................................15 
4. 
Study Design ..................................................................................................................16 
4.1. 
Overall Design ................................................................................................................16 
4.1.1. 
Clinical Hypotheses ........................................................................................................16 
4.2. 
Scientific Rationale for Study Design ............................................................................16 
4.3. 
Justification for Treatment Administration.....................................................................17 
4.4. 
End of Study Definition ..................................................................................................17 
5. 
Study Population ...........................................................................................................18 
5.1. 
Inclusion Criteria ............................................................................................................18 
5.2. 
Exclusion Criteria ...........................................................................................................19 
5.3. 
Lifestyle Considerations .................................................................................................21 
5.4. 
Screen Failures ................................................................................................................21 
6. 
Study Intervention ........................................................................................................22 
6.1. 
Study Interventions Administered ..................................................................................22 
6.1.1. 
Instructions for Use and Administration .........................................................................22 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................22 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................23 
6.4. 
Concomitant Therapy .....................................................................................................23 
6.4.1. 
Washout Before the Study ..............................................................................................23 
6.4.2. 
Rescue Medicine .............................................................................................................23 
6.4.3. 
Prohibited Interventions During the Study .....................................................................23 
6.5. 
Intervention after the End of the Study ...........................................................................24 

 
Approval Date: 
 
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Protocol 1919-802-019  
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................25 
7.1. 
Study Termination ..........................................................................................................25 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................25 
7.2.1. 
Reasons for Discontinuation: Acceptable Terms ............................................................25 
8. 
Study Assessments and Procedures.............................................................................27 
8.1. 
Visit 1 – Screening (Days -60 to -30) .............................................................................28 
8.2. 
Visit 2 – Application Visit (Day 0) .................................................................................28 
8.3. 
Effectiveness Assessments .............................................................................................29 
8.4. 
Safety Assessments .........................................................................................................31 
8.5. 
Other Assessments ..........................................................................................................34 
8.5.5. 
Intranasal Exam (Screening Visit Only) .........................................................................37 
8.6. 
Adverse Events/Adverse Device Effects and Serious Adverse 
Events/Serious Adverse Device Effects .........................................................................37 
8.6.1. 
Time Period and Frequency for Collecting Adverse 
Event/Adverse Device Effect and Serious Adverse Event/Serious 
Adverse Device Effect Information ................................................................................38 
8.6.2. 
Method of Detecting Adverse Events/Adverse Device Effects 
and Serious Adverse Events/Serious Adverse Device Effects .......................................38 
8.6.3. 
Follow-up of Adverse Events/Adverse Device Effects and 
Serious Adverse Events/Serious Adverse Device Effects ..............................................38 
8.6.4. 
Regulatory Reporting Requirements for Serious Adverse 
Events/Serious Adverse Device Effects ..........................................................................39 
8.6.5. 
Pregnancy ........................................................................................................................39 
8.6.6. 
Medical Device Incidents (Including Malfunctions) ......................................................40 
8.6.7. 
Adverse Events of Special Interest .................................................................................41 
8.6.8. 
Medication Errors ...........................................................................................................41 
8.7. 
Treatment of Overdose ...................................................................................................41 
8.8. 
Pharmacokinetics ............................................................................................................42 
8.9. 
Pharmacodynamics .........................................................................................................42 
8.11. 
Health Economics ...........................................................................................................42 
9. 
Statistical Considerations .............................................................................................42 
9.1. 
Statistical Hypotheses .....................................................................................................42 

 
 
Approval Date: 
 
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Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
 
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9.2. 
Sample Size Determination ............................................................................................42 
9.3. 
Populations for Analyses ................................................................................................43 
9.4.1. 
Effectiveness Analyses ...................................................................................................43 
9.4.2. 
Safety Analyses ...............................................................................................................44 
10. 
Supporting Documentation and Operational Considerations ..................................46 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................46 
10.1.1. Regulatory and Ethical Considerations ...........................................................................46 
10.1.2. Financial Disclosure ........................................................................................................46 
10.1.3. Informed Consent Process ..............................................................................................47 
10.1.4. Data Protection................................................................................................................47 
10.1.5. Posting Clinical Study Data ............................................................................................47 
10.1.6. Data Quality Assurance ..................................................................................................48 
10.1.7. Source Documents ..........................................................................................................48 
10.1.8. Study and Site Closure ....................................................................................................48 
10.1.9. Publication Policy ...........................................................................................................49 
10.1.10. Compliance with Protocol...............................................................................................49 
10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................50 
10.3. 
Appendix 3: Abbreviations .............................................................................................56 
10.4. 
Appendix 4: Standard Discontinuation Criteria..............................................................58 
10.5. 
Appendix 5: Study Tabular Summary ............................................................................60 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................62 
Definitions: ....................................................................................................................................62 
Contraception Guidance: ...............................................................................................................62 
Pregnancy Testing: .........................................................................................................................64 
Collection of Pregnancy Information: ...........................................................................................64 
10.7. 
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and Reporting .................................65 
Definitions of a Medical Device Incident ......................................................................................65 
Documenting Medical Device Incidents ........................................................................................66 
Device Deficiency ..........................................................................................................................66 
11. 
References ......................................................................................................................67 
 
List of Tables 
Table 1–1 
Schedule of Visits and Procedures ...................................................................... 7 
Table 8–1 
Effectiveness Assessments ................................................................................ 30 
Table 10–1 
Highly Effective Contraceptive Methods .......................................................... 63 

 
 
Approval Date: 
 
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Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
 
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List of Figures 
Figure 1-1 
Study Schema ...................................................................................................... 6 
Figure 2-1 
Intranasal Tear Neurostimulator System Components ...................................... 12 
Figure 2-2 
Correct Application of the Intranasal Tear Neurostimulator............................. 12 
Figure 2-3 
Schematic Showing Location of Tips for Extranasal Control Application ....... 13 
Figure 8-1 
National Eye Institute/Industry Workshop Scale .............................................. 33 
Figure 8-2 
Ocular Surface Disease Index Questionnaire .................................................... 35 
Figure 8-3 
Target Area of Cotton Swab Nasal Stimulation ................................................ 37 
 
 
 

 
 
Approval Date: 
 
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 Intranas
 
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Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
1.3. 
Schedule of Activities 

 
 
 
 
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CONFIDENTIAL 
Protocol 1919-802-019  
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Protocol 1919-802-019  
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Approval Date: 
 
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Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
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2. 
Introduction 
The Intranasal Tear Neurostimulator (ITN; TrueTear®), was granted a de novo petition by the US 
FDA on May 17, 2018 (
) with the following indications for use: 
• The TrueTear ITN provides a temporary increase in tear production during 
neurostimulation to improve dry eye symptoms in adult patients with severe dry eye 
symptoms. 
2.1. 
Study Rationale 
The ITN delivers small electrical currents to the nasal cavity, stimulating the anterior ethmoidal 
branch of the trigeminal nerve, leading to activation of the nasolacrimal reflex pathway 
responsible for basal and bolus tear production. Numerous studies have been conducted to 
demonstrate that tear production is significantly increased during application of the ITN. 
Tears are a complex aqueous fluid composed of proteins, lipids, and mucins. As the chemical 
composition of tears is essential for their optimized function, it was of interest to determine 
whether or not tears produced during application of the ITN were diluted (ie, reflex tears). 
Studies conducted to date have demonstrated equivalent lipid and protein concentrations in tears 
collected immediately following application of the ITN compared to baseline. In addition, mucin 
secretion stimulated by application of the ITN was suggested in a pilot study (OCUN-003). 
Specifically, a significantly higher ratio of degranulated to non-degranulated conjunctival goblet 
cells post-ITN stimulation was found, suggestive of mucin release. 
This study aims to build on the data collected in the pilot study (OCUN-003) to verify that mucin 
secretion from goblet cells is stimulated with application of the ITN. These data would further 
support the conclusion that the tears stimulated with application of the ITN are representative of 
a complete basal tear as opposed to a diluted reflex fluid.  
2.2. 
Background 
DED is defined as a multifactorial disorder of the ocular surface characterized by loss of tear 
film homeostasis and ocular symptoms, in which tear film instability and hyperosmolarity, ocular 
surface inflammation and damage, and neurosensory abnormalities play etiological roles 
(Craig 2017). An estimated 25 million Americans are reported to have DED, making DED one 
of the most common reasons patients seek care with their eye care professional (Behrens 2006, 
DEWS 2007). 
Signs of dry eye include ocular surface damage, reduced tear volume, delayed tear clearance, 
abnormal tear osmolarity and decreased tear film break-up time. Accompanying symptoms can 
include dryness, grittiness, burning, stinging, discomfort, photophobia and blurry or 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. 

 
 
Approval Date: 
 
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Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
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While progress continues to further our understanding of the underlying pathology of DED and 
corresponding potential targets for treatment intervention, to date treatment of DED remains a 
large unmet medical need (Bielory 2016, Wolffsohn 2017).  
Neuromodulation represents a therapeutic strategy for directly stimulating peripheral neuronal 
connections to attenuate neuronal dysfunction and alleviate symptoms in treating DED. The ITN 
acts via stimulation of the nasociliary nerve (peripheral branch of the trigeminal nerve), 
activating the nasolacrimal reflex through a parallel pathway, acting directly on multiple 
components of the LFU such as lacrimal glands, goblet cells, and meibomian glands 
(LeDoux 2001, Dartt 2009, Bron 2017). Therefore, not only is aqueous production stimulated, 
but also secretion of protein, mucin, and meibum.  
It was recently demonstrated that application of the ITN can trigger both an increase in tear 
volume and goblet cell degranulation in patients with DED (Gumus 2017). Moreover, 
Dieckmann et al demonstrated a significant reduction in the area and size of goblet cells 
immediately after stimulation with ITN, suggesting an increase in mucin secretion 
(Dieckmann 2017). Data reported by Green 2017 and Woodward 2017 have concluded that 
protein and lipid concentration of tears collected post-application of the ITN is equivalent to that 
of tears collected pre-stimulation, suggesting that the ITN promotes release of proteins from 
secretory granules in the lacrimal gland and meibum (lipid) from Meibomian glands. Lastly, 
Pondelis 2017 demonstrated a decrease in the area and perimeter of meibomian glands 
immediately after 3-minute application of the ITN, reinforcing the suggestion that the ITN can 
stimulate lipid secretion. These studies to date demonstrate a clear effect of neurostimulation 
with ITN on all major components of tear film, thus offering a promising new approach for 
treatment of DED. 
2.2.1. 
Device Description 
The ITN is a non-surgical device intended for the application of low level electrical stimulation 
to sensory neurons of the nasal cavities to increase tear production and improve dry eye 
symptoms.  
The device consists of four distinct non-sterile subassemblies, as listed below and shown in 
Figure 2-1: 
1. A reusable base unit which produces the electrical stimulation waveform. 
2. A disposable tip that provides the contact surface for the stimulation to the intranasal skin 
and mucosa. 
3. A reusable charger which recharges the sealed battery inside the base unit. 
4. A reusable cover to protect the disposable tip. 

 
 
Approval Date: 
 
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 Intranas
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Approval Date: 
 
04-Mar-2019
 
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Approval Date: 
 
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Protocol 1919-802-019  
 Intranasal Tear Neurostimulator 
14 
 
The benefit of the ITN is the replenishment of endogenous tears leading to subsequent 
improvement in ocular surface health and dry eye symptoms, thus providing a valuable treatment 
option for patients with DED. 
To date, application of the ITN is safe and well-tolerated and there were no unexpected safety 
concerns. No SADEs have been observed. The most frequently reported ADEs were all related to 
nasal findings consisting of: nasal pain/discomfort (reported as aching, burning, discomfort, pain, 
or soreness), transient intranasal electrical discomfort, nosebleed, and nasal congestion. 

 
 
Approval Date: 
 
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15 
 
3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
To evaluate the change in goblet cell 
degranulation following randomized 
application of device 
• 
Immunofluorescence staining of cells 
obtained via impression cytology 
 
• 
Mean change in goblet cell degranulation post-intranasal 
application of the ITN at the Application Visit compared 
to without-intranasal application of the ITN at the 
Screening Visit.  

 
 
Approval Date: 
 
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16 
 
4. 
Study Design 
4.1. 
Overall Design 
This is a prospective, randomized, controlled, parallel-group, open-label, single-center study in 
participants with DED. 
This study consists of 2 visits: Screening and the Application Visit (Day 0). A study schema is 
located in Section 1.2 and the Schedule of Visits and Procedures is located in Section 1.3. 
Participants will be randomized (in a 2:1 ratio) at Screening to either intranasal or extranasal 
acute (single) application of the ITN, which they will apply accordingly for approximately 3 
minutes during the Application Visit. Approximately 36 participants with DED will be enrolled 
at a single site in the United States. 
At Screening, and prior to any testing, participants will be provided with an IRB-approved ICF 
which they will have the opportunity to review and ask questions about before written consent is 
obtained. The Screening Visit should occur 30 to 60 days prior to the Application Visit. 
The Application Visit will be separated into pre-ITN application and post-ITN application 
assessments. CDVA, slit-lamp examination, TMH measurement via OCT, and tear collection 
will occur at least 45-minutes prior to ITN application, and will be performed again following 
ITN application. Impression cytology will be performed following these procedures after ITN 
application. 
Safety measures will be assessed before and after ITN application at the Application Visit, 
including CDVA and slit-lamp biomicroscopy. AEs will be queried prior to study exit. 
4.1.1. 
Clinical Hypotheses 
Post-application of the ITN, a greater percentage of goblet cells will be degranulated relative to 
pre-application of the ITN as measured by immunofluorescence staining of cells collected by 
impression cytology. 
4.2. 
Scientific Rationale for Study Design 
The ITN stimulates the anterior ethmoidal branch of the trigeminal nerve in the upper nasal 
cavity, leading to an increase in tear production with concomitant increases in proteins and 
lipids. In addition, evidence suggests degranulation of conjunctival goblet cells occurs 
post-application of the ITN. 
Data from Study OCUN-014 demonstrated that tera film protein and lipid concentrations 
post-ITN application were equivalent to those collected prior to ITN application. In a pilot study 
(OCUN-003), participants with DED were assigned to both intranasal and extranasal application 
of the ITN for 3 minutes in random sequence. Results suggested that goblet cell degranulation 
post-intranasal application of the ITN was greater than prior to intranasal application, and that 
intranasal application demonstrated significantly greater goblet cell degranulation relative to 

 
 
Approval Date: 
 
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Protocol 1919-802-019  
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17 
 
extranasal application. In both OCUN-003 and OCUN-014, ITN application demonstrated a 
statistically significant increase in tear production as measured by TMH. While these and other 
studies have provided support for the ITN’s putative mechanisms of action, the effect of 
stimulation on ocular surface pro-inflammatory cytokines has not been clearly established. 
The rationale for this study is to confirm the ITN’s effect on goblet cell release of mucin and to 
explore its effect on tear film cytokine concentration.  
4.3. 
Justification for Treatment Administration 
The ITN will be applied in accordance with the instructions for use. 
4.4. 
End of Study Definition 
The end of study is defined as the date of the Application Visit for the last participant in the 
study, or the AE query on this day for the last participant in the study. 
A participant is considered to have completed the study if he/she has completed both the 
Screening Visit and Application Visit or exited early from the study. 

 
 
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5. 
Study Population 
The study population will consist of adult male and female participants with objective and 
subjective evidence of DED. The study will be conducted at a single site and will enroll up to 36 
participants who have provided written informed consent and have met the eligibility criteria 
below. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Age 
1.01 
Participants must be at least 22 years of age, at the time of signing informed consent 
3. 
Sex 
3.01 
Male and female 
4. 
Informed Consent 
4.01 
Capable of giving verbal and signed informed consent, which includes compliance 
with the requirements and restrictions listed in the ICF and in this protocol 
4.02 
Written informed consent from the participant or legally authorized representative 
has been obtained prior to any study-related procedures 
4.03 
Written documentation has been obtained in accordance with the relevant country 
and local privacy requirements, where applicable. (eg, Written Authorization for Use 
and Release of Health and Research Study Information for the United States) 
5. 
Other 

 
 
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5.01 
Have not worn contact lenses for at least 7 days prior to the Screening Visit and are 
willing to forego the use of contact lenses for the duration of the study 
5.02 
The participants should be literate, able to speak English, and able to complete 
questionnaires independently 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. 
Medical Conditions 
1.01 
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 
1.02 
Have had nasal or sinus surgery (including history of application of nasal cautery) or 
significant trauma to these areas 
1.04 
Have had a corneal transplant in either or both eyes 
1.06 
Have a cardiac demand pacemaker, implanted defibrillator, or other active implanted 
metallic or active implanted electronic device in the head 
1.07 
Have a systemic condition or disease not stabilized or judged by the investigator to be 
incompatible with participation in the study 
2. 
Prior/Concomitant Therapy 

 
 
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2.02 
Have used contact lenses within 7 days prior to the Screening Visit or anticipate the use 
of contact lenses at any time during the duration of the study 
3. 
Prior/Concurrent Clinical Study Experience 
3.01 
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of entry into this study 

 
 
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5. 
Other 
5.01 
Females who are pregnant, nursing an infant, or planning a pregnancy during the study. 
WOCBP who do not agree to use a reliable form of contraception throughout the study. 
5.3. 
Lifestyle Considerations 
No lifestyle consideration restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 

 
 
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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo(s), or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1. 
Study Interventions Administered 
Study Intervention 
TrueTear Intranasal Tear 
Neurostimulator (ITN) – Intranasal 
Application 
TrueTear Intranasal Tear 
Neurostimulator (ITN) – Extranasal 
Application (Control) 
Number and Timing of 
Interventions 
Single application at Application Visit 
Single application at Application Visit 
Manufacturer 
Allergan 
Allergan 
6.1.1. 
Instructions for Use and Administration 
Intranasal Application 
At the Application Visit, participants will be trained on the application of the ITN based on 
approved instructions for use and instructed to administer a single stimulation for approximately 
3 minutes. A sponsor representative may be present for training purposes.  
6.2. 
Preparation/Handling/Storage/Accountability 

 
 
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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
At the time of randomization at the Screening Visit, qualified participants will be randomly 
assigned in a 2:1 ratio to receive either intranasal ITN or extranasal (control) ITN stimulation at 
the Application Visit. Electronic randomization methods will be used to create a randomization 
scheme prior to study start. 
6.4. 
Concomitant Therapy 
The use of any concomitant medication, prescription or OTC, is to be recorded on the 
participant’s CRF at each visit along with the reason the medication is taken. 
At both visits, site staff will question each participant specifically on the use of concomitant 
medications. Site staff must notify the sponsor immediately if a participant consumes any 
concomitant medications not permitted by the protocol. Participants who use(d) prohibited 
concomitant medications may be discontinued from the study at the discretion of the investigator 
or the sponsor. 
6.4.1. 
Washout Before the Study 
Contact lens wear must be discontinued at least 7 days prior to the Screening Visit. 
6.4.2. 
Rescue Medicine 
Rescue medicine is not applicable. 
6.4.3. 
Prohibited Interventions During the Study 
The decision to administer a prohibited intervention is done with the safety of the study 
participant as the primary consideration. When possible, Allergan should be notified before the 
prohibited intervention is administered. Use of the following interventions is prohibited during 
the study: 
• Contact lens wear within 7 days prior to the Screening Visit 
• Punctal or intracanalicular plugs throughout study duration 
• Initiation or change in dosing of any ophthalmic cyclosporine preparations (eg, 
RESTASIS) or lifitegrast 5% ophthalmic solution (Xiidra), any topical ocular glaucoma 
drop, any topical ocular antihistamine drop, or any artificial tear or lubricant ≥ 1 month 
prior to the Screening Visit, or anticipated change during the study. Drops continuing at 
stable dosing (defined as having a start date ≥ 30 days prior to Screening) may continue to 
be used. However, drops should not be used within 2 hours of either study visit. 

 
 
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• Initiation or anticipated change in dosing of any systemic medication (OTC, herbal, 
prescription, or nutritional supplements), which may affect dry eye or vision, ≤ 1 month 
prior to the Screening Visit. Such medications may include, but are not limited to, the 
following: Flax seed oil, fish oil, omega-3 supplements, cyclosporine, antihistamines, 
cholinergic agents, anticholinergics, antimuscarinics, beta blocking agents, tricyclic 
antidepressants, phenothiazines, estrogen, progesterone, and other estrogen derivatives.  
• Use of lid-heating therapy (ie, LipiFlow, iLUX, etc.), meibomian gland probing, or 
therapeutic meibomian gland expression in either eye within 3 months prior to the 
Screening Visit. 
6.5. 
Intervention after the End of the Study 
No interventions after the end of the study are planned. 

 
 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
A premature discontinuation will occur if a participant who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the 
protocol-defined study procedures. 
7.1. 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator. Allergan may 
stop the study (and/or the study site) for any reason with appropriate notification. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
• Participants will be discontinued if they use any prohibited intervention described in 
Section 6.4.3. 
• For participants who discontinue from the study early, every effort should be made to have 
these participants return to the clinical center for completion of the exit visit. AEs leading 
to participant early discontinuation must be followed-up as appropriate. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• See the Schedule of Visits and Procedures (Section 1.3) for data to be collected at the time 
of study discontinuation (early exit). 
7.2.1. 
Reasons for Discontinuation: Acceptable Terms 
A premature discontinuation will occur if a participant who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the 
protocol-defined study procedures. 

 
 
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Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms: 
Commonly Used Terms 
Other Acceptable Terms 
Adverse event 
Death 
Completed 
Failure to meet randomization criteria 
Lost to follow-up 
Progressive disease 
Non-compliance  
Recovery 
Other 
Technical problems 
Physician decision 
Withdrawal by parent/guardian 
Pregnancy 
 
Protocol deviation 
 
Screen failure 
 
Site terminated by sponsor 
 
Study terminated by sponsor 
 
Withdrawal by subject 
 

 
 
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8. 
Study Assessments and Procedures 
Please see the schedule of activities (Section 1.3) for the Schedule of Visits and Procedures 
(Table 1–1). The overall study design is illustrated in Figure 1-1. The visit schedule includes 
2 visits: Screening and Application Visits. Study procedures must be performed in sequence as 
described in the Schedule of Visits and Procedures. 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Visits and Procedures, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• The study will be discussed with the participant and a participant wishing to participate 
must give informed consent prior to any study-related procedures or change in treatment. 
The participants must also give authorization and other written documentation in 
accordance with local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment. 
• Each participant who provides informed consent will be assigned a participant number 
that will be used on participant documentation throughout the study. 
• WOCBP must have a negative pregnancy test result prior to entry into the study, and prior 
to ITN device application at the Application Visit. 
• A participant is considered to have entered the study at the time of randomization during 
the Screening Visit (Day -60 to -30). See Section 6.3 for the method for assignment to 
study intervention groups/randomization. 

 
 
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8.1. 
Visit 1 – Screening (Days -60 to -30) 
8.2. 
Visit 2 – Application Visit (Day 0) 

 
 
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8.3. 
Effectiveness Assessments 
Effectiveness assessments are goblet cell degranulation, TMH, and tear film cytokine 
concentration. 
Timing and measurement details are provided in Table 8–1. 

 
 
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Table 8–1 
Effectiveness Assessments 
Assessment 
Timing 
Measurement 
Goblet cell degranulation 
• 
Screening Visit  
• 
Application Visit after 
randomized ITN 
application 
Impression cytology followed by 
immunofluorescence staining 

 
 
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8.4. 
Safety Assessments 
8.4.1. 
Corrected Distance Visual Acuity 
CDVA is performed at the Screening Visit and Application Visit. At the Application Visit, it is 
performed both prior to and after ITN stimulation. Any changes from baseline should be 
evaluated for possible reporting as an AE. 

 
 
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8.5. 
Other Assessments 
8.5.1. 
Urine Pregnancy Test  
WOCBP will have a urine pregnancy test performed at Screening and the Application Visit. 
Additional details are provided in Appendix 6. 

 
 
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8.5.5. 
Intranasal Exam (Screening Visit Only) 
The nasal cavity is inspected for vascularized polyp, severely deviated septum, severe nasal 
airway obstruction, or evidence of prior surgery/cautery. Any other gross abnormalities or 
irregularities should be documented accordingly. 
8.6. 
Adverse Events/Adverse Device Effects and Serious Adverse 
Events/Serious Adverse Device Effects 
The definitions of an AE/ADE or SAE/SADE can be found in Appendix 2. 
AEs/ADEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE/ADE or SAE/SADE and remain responsible 
for following up AEs/ADEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or study (see 
Section 7). 

 
 
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8.6.1. 
Time Period and Frequency for Collecting Adverse Event/Adverse Device Effect 
and Serious Adverse Event/Serious Adverse Device Effect Information 
All SAEs/SADEs from the signing of the ICF will be collected at the timepoints specified in the 
Schedule of Visits and Procedures (Section 1.3), and as observed or reported spontaneously by 
study participants. 
All AEs/ADEs from the signing of the ICF will be collected at the timepoints specified in the 
Schedule of Visits and Procedures (Section 1.3), and as observed or reported spontaneously by 
study participants. 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent, will be recorded in the AE section of the CRF. 
All SAEs/SADEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix 2. The investigator will submit any updated SAE/SADE data to the 
sponsor within 24 hours of it being available. 
The investigator is not obligated to actively seek AE/ADE or SAE/SADE information after 
conclusion of study participation. However, if the investigator learns of any SAE/SADE, 
including a death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the sponsor. 
The method of recording, evaluating, and assessing causality of AEs/ADEs and SAE/SADEs and 
the procedures for completing and transmitting SAE/SADE reports are provided in Appendix 2. 
8.6.2. 
Method of Detecting Adverse Events/Adverse Device Effects and Serious 
Adverse Events/Serious Adverse Device Effects 
Care will be taken not to introduce bias when detecting AEs/ADEs and/or SAEs/SADEs. Open-
ended and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE/ADE occurrences. 
8.6.3. 
Follow-up of Adverse Events/Adverse Device Effects and Serious Adverse 
Events/Serious Adverse Device Effects 
After the initial AE/ADE/SAE/SADE report, the investigator is required to proactively follow 
each participant at subsequent visits/contacts. All AEs/ADEs/SAEs/SADEs will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-
up. 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Allergan to elucidate 
the nature and/or causality of the AE/ADE or SAE/SADE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 

 
 
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If a participant dies during participation in the study, the investigator will provide Allergan with 
a copy of any postmortem findings including histopathology. 
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated SAE/SADE data to Allergan within 24 hours of receipt 
of the information. 
8.6.4. 
Regulatory Reporting Requirements for Serious Adverse Events/Serious 
Adverse Device Effects 
• Prompt notification by the investigator to the sponsor of an SAE/SADE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
the investigator as necessary. 
• An investigator who receives an investigator safety report describing an SAE/SADE or 
other specific safety information (eg, summary or listing of SAEs/SADEs) from the 
sponsor will review and then file it along with the investigator’s brochure and will notify 
the IRB/IEC, if appropriate, according to local requirements. 
8.6.5. 
Pregnancy 
• If a female study participant becomes pregnant, the investigator should inform Allergan 
within 24 hours of confirming the pregnancy 
 
 Best practices are to be 
followed to ensure the welfare of the participant and the fetus. 
• Once the pregnancy has reached term, the second page of the Pregnancy Surveillance 
Form concerning outcome is to be completed by the investigator and submitted to the 
sponsor. The sponsor will contact the investigator to obtain information about the 
pregnancy outcome. 

 
 
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• Hospitalization for a normal delivery or elective abortion of a normal fetus does not 
constitute an SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered serious. 
Additional details are provided in Appendix 6. 
8.6.6. 
Medical Device Incidents (Including Malfunctions) 
Medical devices are being provided for use in this study for the purposes of evaluating goblet 
cell degranulation produced by nasal neurostimulation. In order to fulfill regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and documentation of 
events meeting the definitions of incident, deficiency, or malfunction that occur during the study 
with such devices, using the Device Deficiency Form.  
The definitions of a medical device incident and a device deficiency can be found in Appendix 7. 
Incidents fulfilling the definition of an AE/ADE/SAE/SADE will also follow the processes 
outlined in Section 8.6.3 and Appendix 2 of the protocol. 
8.6.6.1. 
Time Period for Detecting Medical Device Incidents 
• Medical device incidents, deficiencies, or malfunctions of the device that result in an incident 
will be detected, documented, and reported during all periods of the study in which the 
medical device is used. 
• If the investigator learns of any incident at any time after a participant has been discharged 
from the study, and such incident is considered reasonably related to a medical device 
provided for the study, the investigator will promptly notify the sponsor. 
The method of documenting medical device incidents is provided in Appendix 7. 
8.6.6.2. 
Follow-up of Medical Device Incidents 
• All medical device incidents involving an AE/SAE will be followed and reported in the same 
manner as other AEs (see Section 8.6.3). This applies to all participants, including those who 
discontinue study intervention or the study. 
• The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
• New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator. 
8.6.6.3. 
Prompt Reporting of Medical Device Incidents to Sponsor 
• Medical device incidents will be reported to the sponsor within 24 hours after the investigator 
determines that the event meets the protocol definition of a medical device incident. 

 
 
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• The Medical Device Incident Report Form will be sent to the sponsor by email. If email is 
unavailable, then fax should be used. 
• The same individual will be the contact for the receipt of medical device reports and SAEs. 
8.6.6.4. 
Regulatory Reporting Requirements for Medical Device Incidents and 
Deficiencies 
• The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of incidents to the IRB/IEC. 
8.6.7. 
Adverse Events of Special Interest 
AEs related specifically to impression cytology, including: 
• Conjunctival hyperemia 
• Chemosis (swelling) 
• Discomfort (foreign body sensation, pain) 
• Allergic reaction 
8.6.8. 
Medication Errors 
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows: 
• Wrong study intervention 
• Wrong dose (including dosing regimen, strength, form, concentration, or amount) 
• Wrong route of administration 
• Wrong participant (ie, not administered to the intended participant) 
8.7. 
Treatment of Overdose 
Treatment of overdose is not applicable to this ophthalmology device study. 

 
 
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8.8. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.9. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.11. 
Health Economics 
Health economics are not evaluated in this study. 
9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
For the primary effectiveness analysis of mean change in goblet cell degranulation 
post-intranasal application of the ITN compared to without-intranasal application of the ITN, the 
null and alternative hypotheses are as follows: 
• Null hypothesis: Intranasal application of the ITN is equally effective in improving mucin 
secretion, as measured by the mean change in goblet cell degranulation, post-ITN 
application at the Application Visit versus without-ITN application at the Screening Visit. 
• Alternative hypothesis: Intranasal application of the ITN is not equally effective in 
improving mucin secretion, as measured by the mean change in goblet cell degranulation, 
post-ITN application at the Application Visit versus without-ITN application at the 
Screening Visit. 
9.2. 
Sample Size Determination 
Approximately 36 participants are required to apply randomized device and complete the 
Application Visit, in which 24 participants will be in the intranasal ITN application group and 12 
will be in the extranasal ITN application group. Approximately 50 participants may be enrolled 
to meet this goal. 
It is assumed that the standard deviation of the change in goblet cell degranulation post-ITN 
application versus pre-ITN application is 4.52. With 24 participants in the intranasal ITN 
application group, it is estimated that the accuracy of a half width of the 95% CI is 
approximately 1.8. 

 
 
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9.3. 
Populations for Analyses 
The analysis populations will consist of participants as defined below: 
• The ITT population includes all randomized participants. Participants will be summarized 
according to the randomized study intervention. 
• The safety population includes all treated participants who receive ≥ 1 administration of 
study intervention. Participants will be summarized according to the study intervention they 
actually receive. 
9.4.1. 
Effectiveness Analyses 
The effectiveness analyses will be based on the ITT population. The ITT population is 
considered as the primary analysis population. 
9.4.1.1. 
Primary Effectiveness Endpoint 
• The mean change in goblet cell degranulation post-intranasal application of the ITN at the 
Application Visit compared to without-intranasal application of the ITN at the Screening 
Visit. 

 
 
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9.4.1.3. 
Primary Effectiveness Analyses 
The primary effectiveness variable will be the number of goblet cells degranulated in the study 
eye. The study eye will be the eye with the lower tear meniscus height prior to the application or, 
if both eyes are equal, the right eye. 
The primary effectiveness endpoint will be the mean change in goblet cell degranulation 
post-intranasal application of the ITN at the Application Visit compared to without-intranasal 
application of the ITN at the Screening Visit. Summary statistics of count, mean, median, 
minimum, and maximum will be provided to evaluate the change in the number of degranulated 
goblet cells and a 95% CI will also be provided. 
9.4.1.4. 
Analyses on Exploratory Effectiveness Endpoints 
The other exploratory effectiveness variables will be descriptively summarized by ITN 
application groups. The continuous variables will be summarized with count, mean, standard 
deviation, median, minimum, and maximum. The categorical variables will be presented with the 
count and percentage in each category. 
The details of the statistical analyses and summary methods on each exploratory endpoint will be 
provided in the SAP. 
9.4.2. 
Safety Analyses 
The safety analysis will be performed using the safety population. The numbers and percentage 
of participants reporting AEs will be tabulated regardless of causality. Frequency of device and 
procedure related AEs, as well as AESIs will be summarized. 
9.4.2.1. 
Adverse Events 
An AE or ADE will be considered a TEAE/TEADE if: 
• The AE or ADE began on or after the date of the first application of study intervention; or 
• The AE or ADE was present before the date of the first dose of study intervention, but 
increased in severity or became serious on or after the date of the first application of study 
intervention 
An AE or ADE that occurs more than 30 days after the last dose of study intervention will not be 
counted as a TEAE or TEADE. 
A SAE or SADE will be considered a TESAE or TESADE if it is a TEAE that additionally 
meets any SAE criteria or if it is a TEADE and meets SADE criteria. 
Throughout the course of the study, all AEs will be reported and monitored on an AE CRF, 
including event name, duration, seriousness, relatedness, severity, action taken, and outcome. If 
AEs occur, the first concern will be the safety of the study participants. 

 
 
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All events and device deficiencies are to be recorded on the corresponding CRF for the 
participant upon the site becoming aware of said event. 
TEAEs and TEADEs will be coded with the MedDRA. The number of participants with TEAEs 
and TEADEs will be summarized by study intervention group for SOC and PT. TEAEs and 
TEADEs will also be summarized based on intensity and relationship to study intervention. 
TESAEs and TESADEs will also be summarized by study intervention group for SOC and PT. 
A listing of AEs, ADEs, and pregnancy test results will be also presented. 
The definitions of AE/ADE and SAE/SADE can be found in Appendix 2. 

 
 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
o Applicable ICH/ISO GCP guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

 
 
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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection laws. The level of disclosure must also be 
explained to the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Posting Clinical Study Data 
• Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor.  
• Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required. 
• Company-sponsored study information and tabular study results will be posted on the United 
States National Institutes of Health's website www.ClinicalTrials.gov and other publicly 
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10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed CRFs unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by signing the CRF.  
• The investigator must maintain accurate documentation (source data).  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
• Definition of what constitutes source data can be found in Section 4.0 of ICH E6, GCP: 
Consolidated Guidance and records must be attributable, legible, contemporaneous, original, 
and accurate. 
10.1.8. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. The study site will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 

 
 
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• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
10.1.9. 
Publication Policy 
• Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between investigators and Allergan personnel. 
Authorship will be established prior to the writing of the manuscript. 
• The sponsor will comply with the requirements for publication of study results.  
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements. 
 
 

 
 
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10.3. 
Appendix 3: Abbreviations 
Abbreviation/Term 
Definition 
ADE 
adverse device effect 
AE 
adverse event 
AESI 
adverse event of special interest 
CAM 
Cornea-Anterior Module 
CDISC 
Clinical Data Interchange Standards Consortium 
CDVA 
corrected distance visual acuity 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DED 
dry eye disease 
ECG 
electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
ISO 
International Organization for Standardization 
ITN 
intranasal tear neurostimulator 
ITT 
intent-to-treat 
LED 
light-emitting diode 
LFU 
lacrimal functional unit 
logMAR 
logarithmic minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEI 
National Eye Institute 
OCT 
optical coherence tomography 
OSDI 
Ocular Surface Disease Index 
OTC 
over-the-counter 

 
 
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Abbreviation/Term 
Definition 
PT 
preferred term 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEADE 
treatment-emergent adverse device event 
TEAE 
treatment-emergent adverse event 
TESADE 
treatment-emergent serious adverse device advent 
TESAE 
treatment-emergent serious adverse event 
TMH 
tear meniscus height 
UADE 
unanticipated adverse device effect 
WOCBP 
women of childbearing potential 
 

 
 
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10.4. 
Appendix 4: Standard Discontinuation Criteria 
CDISC Submission Value 
CDISC Definition 
Adverse event 
Any untoward medical occurrence in a patient or 
clinical investigation subject administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be 
any unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal 
(investigational) product, whether or not related to 
the medicinal (investigational) product. For further 
information, see the ICH Guideline for Clinical 
Safety Data Management: Definitions and 
Standards for Expedited Reporting (modified from 
ICH E2A) Synonyms: side effect, adverse 
experience. See also serious adverse event, serious 
adverse experience. (CDISC glossary) 
Completed 
To possess every necessary or normal part or 
component or step; having come or been brought to 
a conclusion (NCI) 
Death 
The absence of life or state of being dead (NCI) 
Disease relapse 
The return of a disease after a period of remission 
Failure to meet randomization criteria 
An indication that the subject has been unable to 
fulfill/satisfy the criteria required for assignment 
into a randomized group 
Lack of efficacy 
The lack of expected or desired effect related to a 
therapy (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to 
follow-up 
Non-compliance with study drug 
An indication that a subject has not agreed with or 
followed the instructions related to the study 
medication (NCI) 
Other 
Different than the one(s) previously specified or 
mentioned (NCI) 
Physician decision 
A position, opinion or judgment reached after 
consideration by a physician with reference to 
subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI) 
Progressive disease 
A disease process that is increasing in extent or 
severity (NCI) 

 
 
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CDISC Submission Value 
CDISC Definition 
Protocol deviation 
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI) 
Recovery 
A healing process and/or an outcome implying 
relative health. The term is typically used in the 
context of direct and indirect effects of sickness or 
injury. (NCI) 
Screen failure 
The potential subject who does not meet one or 
more criteria required for participation in a trial 
Site terminated by sponsor 
An indication that a clinical study was stopped at a 
particular site by its sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by 
its sponsor (NCI) 
Technical problems 
A problem with some technical aspect of a clinical 
study, usually related to an instrument (NCI) 
Withdrawal by parent/guardian 
An indication that a study participant has been 
removed from the study by the parent or legal 
guardian 
Withdrawal by subject 
An indication that a study participant has removed 
itself from the study (NCI) 
 

 
 
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10.5. 
Appendix 5: Study Tabular Summary 
Parameter Group 
Parameter 
Value 
Trial information 
Trial Title 
Goblet Cell Degranulation Produced by 
Nasal Neurostimulation: A Randomized, 
Controlled Study in Patients with Dry Eye 
Disease 
 
Clinical Study Sponsor 
Allergan, Inc. 
 
Trial Phase Classification 
Post-market 
 
Trial Indication 
Dry eye disease 
 
Trial Indication Type 
Exploratory 
 
Trial Type 
Efficacy 
Safety 
 
Trial Length 
1 day, plus the Screening Visit 30 to 
60 days prior to Day 0 
 
Planned Country of Investigational Site 
United States 
 
Planned Number of Participants 
36 
 
FDA-Regulated Device Study 
Yes 
 
FDA-Regulated Drug Study 
No 
 
Pediatric Study 
No 
Participant 
information 
Diagnosis Group 
Dry eye disease 
 
Healthy Participant Indicator 
No 
 
Planned Minimum Age of Participants 
22 
 
Planned Maximum Age of Participants 
N/A 
 
Sex of Participants 
Male or female 
 
Stable Disease Minimum Duration 
Not specified 

 
 
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Parameter Group 
Parameter 
Value 
Treatments 
Investigational Therapy or Treatment 
Intranasal Tear Neurostimulator (ITN) 
 
Intervention Type 
Device 
 
Pharmacological Class of Invest. Therapy 
N/A 
 
Dose per Administration 
3 minutes 
 
Dose Units 
N/A 
 
Dosing Frequency 
Once 
 
Route of Administration 
Intranasal application of ITN 
 
Current Therapy or Treatment 
No 
 
Added on to Existing Treatments 
No 
 
Control Type 
Extranasal application of ITN 
 
Comparative Treatment Name 
ITN 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
2 
 
Trial is Randomized 
Yes 
 
Randomization Quotient 
2:1 (intranasal to extranasal) 
 
Trial Blinding Schema 
Open-label 
 
Stratification Factors 
N/A 
 
Adaptive Design 
No 
 
Study Stop Rules 
None 
 

 
 
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10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
WOCBP 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10–1. 

 
 
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Table 10–1 
Highly Effective Contraceptive Methods 
Female participants of childbearing potential are eligible to participate if they agree to use an 
acceptable method of contraception consistently and correctly. 
Acceptable birth control methods that result in a failure of more than 1% per year include: 

 
 
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10.7. 
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1 for the list of sponsor medical 
devices). 
Medical Device Incident Definition 
• A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/her state of health. 
• Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health 
care personnel. 
It is sufficient that: 
• An incident associated with a device happened. 
AND 
• The incident was such that, if it occurred again, might lead to death or a serious deterioration 
in health. 
A serious deterioration in state of health can include any of the following: 
• Life-threatening illness 
• Permanent impairment of body function or permanent damage to body structure 
• Condition necessitating medical or surgical intervention to prevent one of the above  
• Fetal distress, fetal death, or any congenital abnormality or birth defects 

 
 
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Examples of Incidents 
• A participant, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse. 
• A participant’s study intervention is interrupted or compromised by a medical device failure. 
• A misdiagnosis due to medical device failure leads to inappropriate intervention. 
• A participant’s health deteriorates due to medical device failure. 
Documenting Medical Device Incidents 
Medical Device Incident Documenting 
• Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical practice, 
and on the appropriate form of the CRF. 
• For incidents fulfilling the definition of an AE/ADE or an SAE/SADE, the appropriate 
AE/ADE or SAE/SADE CRF page will be completed as described in Appendix 2. 
• The CRF will be completed as thoroughly as possible and signed by the investigator before 
transmittal to the sponsor or designee. 
• It is very important that the investigator provides his/her assessment of causality (relationship 
to the medical device provided by the sponsor) at the time of the initial AE/ADE or 
SAE/SADE report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident. 
• A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident. This includes any 
amendment to the device design to prevent recurrence. 
Device Deficiency 
A device deficiency is defined in accordance with ISO 14155 as inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, safety, or performance. Device 
deficiencies include malfunctions, use errors, and inadequate labeling. 
If a device deficiency occurs, the investigator will notify the sponsor using the fax number or 
email on the front page of the protocol. Device deficiencies shall be documented throughout the 
study and appropriately managed by the sponsor. The sponsor shall review all device 
deficiencies and determine and document in writing whether they could have led to an SADE. 
These shall be reported to the regulatory authorities and IRBs/IECs as required by national 
regulations. 

 
 
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11. 
References 
Behrens A, Doyle JJ, Stern L, Chuck RS, McDonnell PJ, Azar DT, et al. Dysfunctional tear 
syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25(8):900-907. 
Bielory BP, Shah SP, O’Brien TP, Perez VL, Bielory L. Emerging therapeutics for ocular 
surface disease. Curr Opin Allergy Clin Immunol. 2016;16(5):477-486. 
Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II 
pathophysiology report. Ocul Surf. 2017;15(3):438-510. 
Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK. TFOS DEWS II Definition and 
Classification Report. Ocul Surf. 2017;15(3):276-283. 
Dartt DA. Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases. 
Prog Retin Eye Res. 2009;28(3):155–177. 
DEWS. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the 
International Dry Eye Workshop (2007). Ocul Surf. 2007;5(2):93-107. 
Dieckmann G, Kataguiri P, Pondelis N, Jamali A, Alessandro A. In vivo confocal microscopy 
demonstrates intranasal neurostimulation-induced goblet cell alternations in patients with dry eye 
disease. ARVO Oculeve 2017. 
Green KB, Kamat M, Franke M, Holdbrook M, Senchyna M. Tear total lipid concentration in 
patients with dry eye following intranasal neurostimulation. ARVO Oculeve 2017. 
Gumus K, Schuetzle K, Pflugfelder SC. Randomized controlled crossover trial comparing the 
impact of sham or intranasal tear neurostimulation on conjunctival goblet cell degranulation. Am 
J Ophthalmol. 2017;177:159–168. 
LeDoux MS, Zhou Q, Murphy RB, Greene ML, Ryan P. Parasympathetic innervation of the 
meibomian glands in rats. Investig Ophthalmol Vis Sci. 2001;42(11):2434-2441. 
Pondelis NJ, Dieckmann G, Kataguiri P, Abbouda A, Franke M, Senchyna M, et al. Intranasal 
neurostimulator induces morphological changes in meibomian glands in patients with dry eye 
disease. ARVO Oculeve 2017. 

 
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Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II 
Diagnostic Methodology report. Ocul Surf. 2017;15(3):539-574. 
Woodward AM, Senchyna M, Franke M, Holdbrook M, Argüeso P. Effect of intranasal 
neurostimulation on tear protein content in patients with dry eye. ARVO Congress 2017. 

 
 
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Signed by: 
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1919-802-019 Protocol
04-Mar-2019 15:23 GMT-080
Clinical Development Approval