Assessing the Efficacy of Intranasal Neurostimulation in Ameliorating Symptoms of Neuropathic Corneal Pain
Phase: NA
Conditions: Cornea
Sponsor: Tufts Medical Center

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COVER PAGE 
 
 
Clinical Protocol Title:  
Assessing the Efficacy of Intranasal Neurostimulation in Ameliorating Symptoms of 
Neuropathic Corneal Pain 
 
Version number and date: Version 1, July 20, 2018  
Phase of clinical investigation: Pilot study 
IND/IDE number: N/A 
Investigational device:  
TrueTear® Intranasal Neurostimulator (Allergan) 
Regulatory Sponsor:   
Pedram Hamrah, MD   
Funding Sponsor: N/A 
Study Monitor 
Medical Director:  N/A 
Investigator(s): 
Pedram Hamrah, MD 
Tufts Medical Center 
800 Washington Street 
Boston, MA 02111 
Phone: 617-636-5720 
Email: PHamrah@tuftsmedicalcenter.org 
 
 
 

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Acronym List: 
 
 
NCP- Neuropathic corneal pain 
TG- Trigeminal ganglion 
ITN- Intranasal Neurostimulator 
NLR- Nasolacrimal reflex 
IVCM-In vivo confocal microscopy 
VAS- Visual analogue scale  
CRF- Case report form 
BVCA- Best correct visual acuity 
TBUT- Tear break-up time 
OSDI- Ocular surface disease index 
OPAS- Ocular pain assessment survey 
IDEEL- Impact of Dry Eye on Everyday Life 
AE – Adverse Event 
SAE- Serious adverse effect 
UADE - Unanticipated Adverse Device Effect 
 

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Table of Contents 
Contents 
COVER PAGE 
1 
STUDY DESIGN SCHEMATIC 
4 
1. CLINICAL PROTOCOL 
5 
2. STUDY OBJECTIVES 6 
3. STUDY DESIGN 7 
4. SUBJECT SELECTION 8 
5. STUDY DEVICE 9 
6. BIOSPECIMEN COLLECTION (IF APPLICABLE) 12 
7. STUDY PROCEDURES 13 
8. SAFETY AND EFFECTIVENESS ASSESSMENTS 17 
9. ADVERSE EVENT RECORDING AND REPORTING 
18 
10. STATISTICAL METHODS/DATA ANALYSIS 
20 
11. DATA AND SAFETY MONITORING 
22 
12. DATA HANDLING, RECORD-KEEPING AND MONITORING 23 
13. STUDY DISCONTINUATION CRITERIA  24 
14. REFERENCES   25 
14. APPENDICES   26 

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Assessing the Efficacy of Intranasal Neurostimulation in Ameliorating Symptoms of 
Neuropathic Corneal Pain 
 
 
STUDY DESIGN SCHEMATIC 
__________________________________________________________________ 
 
 
 
 
1. CLINICAL PROTOCOL 
______________________________________________________________ 
 
1.1. Background/ Rationale: 
Neuropathic corneal pain, like neuropathic pain elsewhere in the body, is defined as pain 
resulting from a lesion/injury affecting the corneal somatosensory system on the ocular surface 
[1]. The increased numbers of patients with refractory corneal pain and discomfort following 
refractive surgery [2], and among patients with dry eye disease [3], has resulted in increased 

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interest by ophthalmologists and scientists to investigate the underlying mechanisms involved in 
NCP, and to search for new treatments to ameliorate neuropathic pain. 
 
The cornea is highly innervated with sensory nerves, A- and C- fibers that originate from the 
ophthalmic branch of the trigeminal nerve. These nerves end in the corneal epithelium as free 
terminals [4]. These free nerve endings are classified as different types of nociceptors, depending 
on their responses to stimuli [5, 6].  
 
Corneal pain signals are transmitted to the primary afferent fibers in the trigeminal ganglion 
(TG). From there second-orders neurons join the contralateral spinothalamic tract to synapse 
with third-order neurons in the thalamus. These ascending signals are further modified by input 
from subcortical structures associated with emotions and memory before terminating in the 
somatosensory cortex where they are felt as pain [7].  
 
Injury to corneal nerves, associated with inflammatory responses may result in peripheral 
sensitization, which involves a decrease in nociceptor threshold for excitation, resulting in pain 
responses to typically non-painful stimuli (hyperalgesia) or even in the absence of stimuli 
(allodynia). Persistent nerve injury leading to prolonged and continuous signaling through the 
afferent fibers may subsequently lead to central sensitization, in which nociceptors outside the 
site of the original lesion undergo a similar process and can be activated by sub-threshold stimuli 
or even spontaneously discharge independent of any peripheral signaling [8, 9]. 
 
Peripheral neuromodulation involves applying electrical currents to peripheral nerves for medical 
therapy. Its evolution and expansion has increased over the course of the last two decades for the 
management chronic pain [7, 10]. The “gate control theory” provides the understanding for this 
concept, by which activation of large myelinated nerve fibers inhibits transmission of pain 
impulses from the peripheral nervous system to the central nervous system. The antegrade 
stimulation of nociceptive A nerve fibers leads to activation of interneurons in the TG. The 
same interneurons in the TG are also involved in the process of transmission of nociceptive 
signals from peripheral nerves. Non-painful stimuli from peripheral nerves, such as those 
conducted with the ITN, result in decreased excitability, increased electrical thresholds, transient 
slowing of conduction velocity, and result in inhibition of interneurons that leads to interruption 
of pain signal transmission from the territory innervated by the stimulated nerve [11, 12].  
  
The TrueTear® ITN, recently approved by the FDA, is a portable neuromodulation device that 
delivers a small electrical current to the sensory nerves in the nasal cavity that stimulates the 
nasolacrimal reflex (NLR) [13]. The NLR afferent pathway emerges from the ethmoidal nerve, a 
subunit of the ophthalmic branch of the trigeminal nerve and ends at the interneurons in the TG. 

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2.0 STUDY OBJECTIVES 
_________________________________________________________________ 
 
Hypothesis / Study Objective/ Purpose: 
 
In our recent study using the TrueTear™ intranasal neurostimulator (ITN) in patients with dry 
eye disease (Dieckmann et al. ARVO 2017, unpublished observation) and concurrent 
neuropathic symptoms, some patients that suffered from neuropathic pain or photoallodynia, 
reported immediate relief of pain or photoallodynia after a single 3-minute use of ITN. 
 
Thus, we hypothesize that the stimulation through the ethmoidal nerve in the nasal cavity may 
have an inhibitory effect on the primary TG interneurons and block the ocular pain signaling to 
the brain. 
 
We propose a non-randomized, cross sectional, open-label, single arm pilot trial for treatment of 
neuropathic corneal pain (NCP) with ITN with the following specific aims: 
 
Specific Aims:   
1. To elucidate the efficacy of ITN in ameliorating pain among neuropathic corneal pain 
patients. 
2. To elucidate the safety, efficacy, longevity of ITN in ameliorating pain among 
neuropathic corneal pain patients during a 90-day period with daily use. 
3. To assess quality of life changes by treating neuropathic corneal pain with ITN during a 
90-day period with daily use. 
 
 

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3.0 STUDY DESIGN 
 
3.1. Study Design Description 
 
This study is a prospective, interventional, open-label, single arm, non-randomized trial treating 
45 patients with peripheral or mixed neuropathic corneal pain at their baseline exam and 
following 45 days and 90 days of daily use with the TrueTear™ ITN device. 
 
 
3.2 Statistical analysis: 
Two-tailed paired sample t-test and Pearson correlation will be performed for pain intensity, and 
to assess associations between different quality of life scores. Statistical comparisons of the mean 
values between different groups based will be performed using ANOVA. 
The normality of continuous variables will be tested with the Shapiro-Wilk test. All tests will be 
two tailed and statistical significance will be considered for p values of less than 0.05. 
 
 
 
 
 

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4.0 SUBJECT SELECTION 
__________________________________________________________________ 
 
 
4.1. Subject Inclusion Criteria: 
 
1. Age ≥22. 
2. Ability to consent to study. 
3. Symptoms of neuropathic corneal pain for at least 3 months, such as burning, stinging, 
light sensitivity, discomfort or pain. 
4. Positive in vivo confocal microscopy (IVCM) findings for NCP such as presence of 
microneuromas and decreased nerve density. The presence of positive IVCM findings 
serves in lieu of skin biopsies as proof of nerve injury. 
5. Fifty percent or more relief of pain or discomfort after instillation of Proparacaine eye 
drops as measured by the Visual Analogue Scale (VAS). 
 
4.2. Subject Exclusion Criteria: 
 
1. Clinically significant acute ocular surface diseases, such as active infectious keratitis or 
recent ocular surgery in the past 3 months. 
2. Chronic or recurrent epistaxis, coagulation disorders. 
3. Nasal or sinus surgery or significant trauma to the nose. 
4. Severe nasal airway obstruction or vascularized nasal polyps. 
5. Cardiac demand pacemaker, implanted or wearable defibrillator, or other implanted 
electronic device in the head or neck. 
6. Chronic or recurrent nosebleeds 
7. Bleeding disorder or another condition that can lead to increased bleeding 
8. Known hypersensitivity (allergy) to the hydrogel material that contacts the nasal mucosa 
9. Disabling arthritis, neuropathy, or limited motor coordination affecting self-handling of 
the device. 
10. Allergic to benzalkonium chloride  (the Co-Investigators who administer the eye drops 
ask all patients if they are allergic to any eye drop preservatives before proceeding with 
the eye drops) 
 
 
 
 

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5. STUDY DEVICE 
 
5.1 Study Device Information 
The ITN delivers small electrical currents to the inner cavity of the nose, gently activating nerves 
that stimulate the body’s natural tear production system. 
The device consists of four distinct parts (Figure 1): 
1. 
A reusable Base Unit, which produces the electrical stimulation waveform. 
2. 
A disposable Tip Assembly that inserts into the nasal cavity and stimulates the target 
intranasal tissue. 
3. 
A reusable Cover to protect the Tip Assembly. 
4. 
A Charger, which recharges the battery inside the Base Unit. 
 
 
 
 
Figure 1: The TrueTear® Intranasal Neurostimulator (ITN) components. 
 
1. Base Unit 
When activated, the base unit provides electrical pulses to the Tip Assembly. The strength of 
these pulses is controlled by two buttons, with five different levels available, indicated by the 
number of illuminated LEDs on the base unit. The Base Unit can only be activated when a Tip 
Assembly is present. The base unit also records the use of the device, stimulation level and 

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duration, in internal memory. Upon return of the device, this information will be downloaded 
from the device and summarized as described in the Statistics section below. 
 
2. Tip Assembly 
The Tip Assembly is specially designed to allow the participant to easily apply stimulation to the 
target areas within the nose. The Tip Assembly connects to the Base Unit and contains a 
hydrogel (similar to the material used in contact lenses) that touches the inside of the nose to 
provide stimulation. The disposable Tip Assemblies are removed and replaced at least daily; a 
separate Cover can be used to protect the Tip Assembly when not in use. 
 
3. Cover 
The cover may be slipped over the top of the Base Unit and Tip Assembly between uses. 
 
4. Charger 
The Base Unit may be recharged by removing the Tip Assembly and placing it onto the Charger.  
Charging takes under 4 hours, and a green LED indicates that the process has completed.  
 
5. Device Accountability 
The investigator will be responsible for maintaining a device accountability log(s) that will track 
device usage for all study participants.  Information tracked will include date of device receipt, 
lot and/or serial number, date of device usage or return (if applicable), subject ID, the occurrence 
of any device malfunctions or failures.  
 
6. Labeling, Packaging, Storage, and Return or Disposal of Study Devices 
All devices will be stored and maintained in accordance with package directions. Non-disposable 
devices should be returned to the Sponsor at the conclusion of the study. Used disposable devices 
should be discarded after use; unused disposable devices should be returned to the Sponsor at the 
conclusion of the study. 
 
5.2   Study Device Compliance/Adherence  
 
Directed questioning using the (Ocular Tolerability and Compliance Questionnaire – Appendix 
VI) will be administerd by the investigator or research staff. Results on the participants’ 
compliance and adherence to the study protocol and study device will be recorded on the paper 
case report form (CRF). During the study, all concomitant medication treatment regimens, ocular 
hygiene treatments (i.e., lid scrubs and warm compresses), or insertion of punctal plugs will be 
kept constant as permitted by accepted medical practice. If one of the aforementioned treatment 
regimens needs to be modified, the participant may be withdrawn based on the investigator’s 
discretion. 
 
Participants must be compliant with IVCM  imaging on the study visit or they will be withdrawn. 
Subjects who are withdrawn may be replaced by new enrolled subjects to maintain the sample 
size. 
 
5.3   Clinical procedures and training 
  Study procedure and device training 

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Device application using the ITN 
Participants will be trained on how to use the ITN properly. 
Shortly thereafter, participants will be instructed to place the tips of the ITN into both nostrils 
simultaneously (Figure 2). Participants will be asked to apply and control the intensity of 
stimulation by pressing the plus (+) or minus (-) buttons on the device. The level of intensity will 
be chosen and controlled by the participant. The level of intensity used may be between 2 and 5 
out of a possible 5 levels. Each participant will be asked to apply application for 1 minute should 
no change in discomfort been noted after 1 minute and 3 minutes. Participants will also be told 
they can control the location of stimulation by the depth and angle of insertion until they feel a 
“tickle” sensation. Participants will be told they can cease stimulation by pressing the minus 
button on the Base Unit or by withdrawing the entire ITN device from the nostrils. 
 
Patients will use the TrueTear® a minimum of at least twice a day. The patient is allowed to use 
it more often than twice a day if needed.   
 
 
 
Figure 2: Use of the TrueTear® Intranasal  Neurostimulator (ITN).  
Turning on the device and placing it into the nose 
 
 
5.4 
Quality control and quality assurance 
The collection of accurate, consistent, complete, and reliable data will be assured through the use 
of training sessions, monitoring of the investigator by qualified personnel, data verification, and 
cross-checking.   
 
 

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6. BIOSPECIMEN COLLECTION (IF APPLICABLE) 
________________________________________________________________ 
 
 
6.1 Specimen preparation, handling, and shipping: N/A 
 
6.2 Instruction for specimen preparation, handling and storage: N/A 
 
6.3 Specimen shipment: N/A 
 
6.4 Future use of stored specimens: N/A 
 

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7. STUDY PROCEDURES 
__________________________________________________________________ 
 
 
7.1 Screening/Baseline Procedures 
 
Prospective participants, as defined by the inclusion/exclusion criteria, will be considered for 
entry into this study. Concurrent enrollment of subjects who are participants in other studies will 
be allowed based on the investigator’s discretion. 
 
During the consent process, study design and treatment regimen will be discussed with each 
subject. Written informed consent will be obtained before any study specific procedures are 
performed. However, standard of care clinical information (such as: medical history, BCVA, 
TBUT, staining, and Schirmer’s test) obtained during a subject’s clinical visit within the 
previous 48 hours can be used during the screening visit to determine eligibility and as their 
baseline assessments.  
 
The following evaluations and procedures will be performed for all subjects during the screening 
period: 
 Written informed consent 
 Record of current ocular and systemic medications 
 Record of significant medical/surgical history in the past 5 years 
 Record of demographic data, including date of birth, sex, and race/ethnicity 
 Eye examination (best corrected visual acuity, slit-lamp biomicroscopy, introcular 
pressure) 
 Corneal fluorescein staining 
 Conjunctival lissamine green staining 
 Tear break-up time (TBUT) 
 Corneal in vivo confocal microscopy (IVCM) 
 Ocular Surface Disease Index (OSDI) questionnaire 
 Ocular Pain Assessment Survey (OPAS) questionnaire 
 IDEEL QoL Questionnaire  
 
 The following evaluations and procedures will be performed for all subjects during the 
Enrollment/Baseline procedures (once the patient is confirmed to be eligible):Visual 
Analogue Scale (VAS) questionnaire before and after each of the five tests (filter glasses 
response, hyperosmolar saline response, cold saline response, proparacaine challenge 
test)Schirmer’s test II (with anesthesia) 
 
The description of the procedures is as follows: 
Ocular Surface Disease Index (OSDI) questionnaire: (Appendix I) 12-item questionnaire 
designed to provide a rapid assessment of the symptoms of ocular irritation consistent with dry 
eye disease and their impact on vision-related functioning. The 12 items of the OSDI 
questionnaire are graded on a scale of 0 to 4, where 0 indicates none of the time; 1, some of the 

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time; 2, half of the time; 3, most of the time; and 4, all of the time. The total OSDI score is then 
calculated on the basis of the following formula: OSDI= [(sum of scores for all questions 
answered) x  ]/[(total number of questions answered) x 4]. 
 
Ocular Pain Assessment Survey (OPAS): OPAS Questionnaire (Appendix III): 27-item 
quantitative questionnaire designed to provide an assessment of the symptoms and quality of life 
effect of ocular pain. The 27 items of the OPAS questionnaire are graded on a scale of 0 to 10, or 
10 to 100, where 0 indicates none and 10 or 100 indicate maximum.   This questionnaire should 
take approximately 2-3 minutes to complete. 
 
Visual Analogue Questionnaire: (Appendix IV) Symptoms of ocular comfort and dryness will 
be graded for each eye on a scale of 0-100, where 0=extremely uncomfortable, extremely dry 
and 100=excellent comfort, no dryness. An average rating will be provided for the morning, 
afternoon and evening.  This questionnaire should take approximately 2-3 minutes to complete. 
 
IDEEL QoL Questionnaire (Appendix V): This is a 27-item questionnaire, designed 
specifically for DED and is divided into three parts. It assesses the quality of life in three aspects 
of life for the previous 2 weeks: daily activities, work and feelings. The quality of life is assessed 
on a scale of 0-5, with zero being inability to do the activity. The score is calculated between 0 – 
100 with higher scores indicating a better quality of life. This questionnaire should take about 5-
10 minutes complete. 
 
Filter glasses: This test will be done in a dimly lit room, about 50 lumens of light intensity 
(approximately 50-75 square feet room with 10 lumens per square feet), room temperature, 
pressure and humidity. Each eye will be assessed separately. The other eye will be covered with 
an occluder to eliminate exposure to the light. The study eye will be covered using a 100% 
opaque filter and then the opacity of the filters will be reduced in decrements of 10%. Ten graded 
filters have been developed for this purpose; each of these filters decrease light opacity by 10%. 
Light will be shone at a distance of approximately 10 cm from the eye, using a mussel light 
(halogen fiber-optic transilluminator). Starting at the 100% opaque filter, the filter at which the 
patient starts to feel pain/photophobia will be noted. That light level will be used to assess 
threshold and a pain/photophobia for each filter will be noted on a scale of 1-10. Using pilot 
studies we have seen that the pain/burning can increase with an increase in light in patients with 
NCP. 
 
Cold Response Test: One drop of cold 0.9% preservative-free saline eye drops will be topically 
applied onto the patient’s eyes. The level of discomfort/pain will be assessed by the VAS 
questionnaire before and after the drops are applied. 
 
Hyperosmolatity Response: One drop of 5% sodium chloride (Muro 128® 5%) drop will be 
topically applied on the conjunctival fornix of both eyes. The level of discomfort will be 
measured the VAS questionnaire before and after application of a 5% sodium chloride drop. 
 
Proparacaine Challenge Test: One drop of Proparacaine Hydrochloride Ophthalmic Solution 
0.5% will be topically applied in both eyes to differentiate between the peripheral versus central 

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component of the patient’s pain or discomfort.  The level of discomfort/pain will be assessed by 
the VAS questionnaire. 
 
Schirmer’s (II) Test with Anesthesia: The Schirmer’s test will be performed 3 minutes after a 
drop of topical anesthesia with 0.5% proparacaine (Alcon Inc., Ft Worth TX) is applied to the 
eye. The Schirmer test is performed by placing a narrow filter-paper strip (5 x 35 mm strip of 
Whatman #41 filter paper) in the inferior cul-de-sac. This test is to be conducted in a dimly lit 
room. The subject should gently close their eyes until five minutes have elapsed and the strips 
are removed. Since the tear front will continue advancing a few millimeters after it has been 
removed from the eyes, it is important to mark the tear front with a ball-point pen at precisely 
five minutes. Aqueous tear production will be measured by the length in millimeters that the strip 
wets during 5 minutes.  This procedure should take approximately 10 minutes to complete. 
 
Tear Break-Up Time (TBUT): The standard TBUT measurement will be performed by 
dropping a fluorescein drop to the inferior tarsal conjunctiva. After several blinks, the tear film 
will be examined using a broad beam of the slit lamp with a blue filter. The time lapse between 
the last blink and the appearance of the first randomly distributed dark discontinuity in the 
fluorescein stained tear film will be measured three times and the mean value of the 
measurements will be calculated. The tear break-up time will be evaluated prior to the instillation 
of any eye drops and before the eyelids are manipulated in any way. Break-up times less than 10 
seconds are considered abnormal. A positive change from baseline indicates improvement.  This 
procedure should take approximately 10 minutes total to complete. 
Corneal Fluorescein Staining: (Appendix II) Corneal fluorescein staining will be performed 
after 3 minutes of application of a fluorescein drop. The entire cornea will be then examined 
using slit-lamp evaluation with cobalt blue illumination. Staining will be graded using the NEI 
grading scheme, with a total range of 0-15.  
 
Conjunctival Lissamine Green Staining: (Appendix II) Grading of conjunctival lissamine 
green staining will be performed after 2 minutes of application of a lissamine green drop. The 
nasal and temporal conjunctiva will be examined using slit-lamp evaluation with white light. 
Staining will be graded using the NEI grading scheme, with a total range of 0-18.   This 
procedure should take approximately 2 minutes to complete. 
In Vivo Confocal Microscopy (IVCM): In vivo confocal microscopy (IVCM) is a new imaging 
method, which allows visualization of the corneal structures at the cellular level. With a 
magnification of 800 times, it makes it possible to detect and quantify changes in the epithelial 
layers and sub-basal nerve plexus.  
 
7.2 Study Visit 
The study will be performed in four visits. During the baseline visit, all patients will be evaluated 
using the flowchart (page 2). The first visit will include in-office testing of ITN and response to 
ITN. After 45 days (6 weeks ± 1 week) and 90 days (3 months ± 2 weeks) of using the ITN on a 
daily basis, the patients will return for follow-up visits. The same flowchart as for screening visit 
will be followed in these two visits (with the exception confocal microscopy on visit 2). 
Additionally, evaluation of diary for daily use (Appendix VII) and questionnaires regarding 

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tolerability and safety of device and any reduction in the use of concomitant pain medications 
will be assessed on these visits.   
 
7.3 Standard of Care Procedures 
The following procedures are the standard of care: 
 Ocular Surface Disease Index Questionnaire (OSDI) 
 OPAS 
 VAS 
 Eye examination (best corrected visual acuity, bio-microscopy, intraocular pressure 
measurement) 
 Schirmer’s II test (may be study specific) 
 Tear break-up time (TBUT) 
 Corneal fluorescein staining 
 Conjunctival lissamine green staining 
 Central corneal in vivo confocal microscopy 
 
7.4 Study Specific Procedures: 
At the study visit, the following procedures will be performed for study specific purposes in 
addition to standard of care procedures: 
 Questionnaires: OPAS, VAS after ITN, IDEEL, Safety and tolerability questionnaires 
 ITN response at 1 minute and 3 minutes to assess pain and light sensitivity 
 Diary to keep readings (Appendix VII) 
 Schirmer’s test with anesthesia (may be standard of care) 
 Filter glasses test 
 Cold saline solution response 
 Hypertonic saline solution response 
 Proparacaine challenge test (may be standard of care) 
 
7.4 Follow-up Procedures  
Subjects will come back for a 1st visit after the screening visit; 2nd visit at 45 days (± 1 week) 
following the first visit, and 3rd visit following 90 days after the first visit (± 2 weeks).  All of the 
procedures done at the baseline visit will be done in the 2nd and 3rd visits (see flowchart).   
 
In addition, subjects will be asked about their usage of the ITN. Ocular safety and tolerability 
questionnaire (appendix VI) will be administered in the 2nd and 3rd visit. The subject will be 
asked to complete a diary every day to record any pain symptoms (Appendix VII). The subject 
will be asked to send their pain diary weekly to the study coordinator, in however method works 
for the subject to ensure compliance with the ITN. They will also need to bring the diary to each 
study visit, to ensure compliance.  
 
Ocular Tolerability Questionnaire (Appendix VI): This questionnaire assesses tolerability of 
the ITN device. It assesses symptoms of discomfort in each eye after ITN use.  
 
7.5 Unscheduled Visits 
 

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If the subject reports to the Cornea Department for a visit that is not related to the study, only a 
review of adverse assessments will be required per the study.  
 
7.6 Early Termination 
 
If a subject withdraws or is withdrawn from the study prior to completion of all study visits, 
there will be no additional procedures performed  
8. SAFETY AND EFFECTIVENESS ASSESSMENTS 
_______________________________________________________________ 
 
8.1 Safety Assessments 
The primary safety variable monitored will be the occurrence of adverse events. The severity of 
each adverse event observed will be evaluated as serious or not serious and the occurrence will 
be evaluated as expected or unexpected. The relationship of the event to the study medication 
will be assessed by the investigator as possibly, probably, or definitely related. Safety variables 
will be evaluated at all study visits. If adverse events occur, the first concern will be the safety of 
the study participants. Any serious adverse event occurring during the study period will be 
immediately reported to TUFTS IRB. At each visit throughout the study, the investigator will 
begin querying for adverse events by asking each subject a general, non-directed question such 
as “How have you been feeling since the last visit?” or “How have your eyes been since the last 
visit?” 
A comprehensive eye examination including best-corrected visual acuity, evaluation of the 
condition of conjunctiva, cornea, anterior chamber, iris/pupil, lens, will be performed.  
Withdrawal from the study will happen if any of the following occurs: 
 Investigator determination that it is not in the best interest of the subject to continue 
participation.          
 Subject’s wish to withdraw for any reason. 
After being withdrawn, subjects will be followed according to each case until the adverse event 
is resolved. 
 
 

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9. ADVERSE EVENT RECORDING AND REPORTING 
______________________________________________________________ 
 
 
9.1 Recording Requirements 
 
Adverse Events (AEs) 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, regardless of causal attribution.  
 
Serious Adverse Events (SAEs) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 Is fatal (i.e., the adverse event actually causes or leads to death) 
 Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
 
Unanticipated Problems  
According to the Office of Human Research Protections (OHRP), unanticipated problems 
includes “any incident, experience, or outcome that meets all of the following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; 
2. related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved in the 
research); and 
3. suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
Unanticipated Adverse Device Effect (UADE)  
Unanticipated adverse device effect means any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
 
Research subjects will be routinely questioned about adverse events at study visits. All observed 
or volunteered adverse events (serious or non-serious) and abnormal test findings, regardless of 
study group or suspected causal relationship to the study device(s) will be recorded in the 
subjects’ case histories (source data, case report form).  For all adverse events, sufficient 
information will be pursued and/or obtained so as to permit 1) an adequate determination of the 
outcome of the event (i.e., whether the event should be classified as a serious adverse event) and; 
2)  an assessment of the causal relationship between the adverse event and the study device.    

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Adverse events or abnormal test findings thought to be associated with the study device (ITN) 
will be followed until the event (or its sequel) or the abnormal test finding resolves or stabilizes 
at a level acceptable to the Investigator. 
An abnormal test finding will be classified as an adverse event if one or more of the following 
criteria are met: 
 
 The test finding is accompanied by clinical symptoms 
 The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other therapy  
 The test finding is considered an adverse event by the Investigator. Note: simply 
repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse event.   
 
The Investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study device; and 3) if the 
adverse event meets the criteria for a serious adverse event. 
If the Investigator’s final determination of causality is “unknown and of questionable 
relationship to the study device”, the adverse event will be classified as associated with the use 
of the study device for reporting purposes.  If the Investigator’s final determination of causality 
is “unknown but not related to the study device”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history (source data or case 
report form).  
 
 
9.2   REPORTING PROCEDURES 
 
 REPORTING OF ADVERSE EVENTS TO FDA 
 Unanticipated Adverse Device Effect (UADE) will be reported to the sponsor and the IRB 
within 5 business days after investigators first learns of the event.  
 
Reporting Adverse Events to Other External Entities 
Therefore no reports on adverse events will be submitted to external entities. 
 
 Reporting Adverse Events to the Human Studies Committee 
TUFTS policy for “REPORTING ADVERSE EVENTS AND UNANTICIPATED PROBLEMS” 
will be followed. 
 
9.3   Withdrawal of Subjects due to Adverse Events 
 
Withdrawal from the study will happen if any of the following occurs: 
 Investigator determines that is not in the best interest of the subject to continue 
participation. 
 Subject’s wishing to withdraw for any reason. 
 

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After being withdrawn, subjects will be followed according to each case until the adverse event 
is resolved. 
 
 

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10. STATISTICAL METHODS/DATA ANALYSIS 
__________________________________________________________________ 
10.1   Primary endpoint(s) or outcome measure(s) 
 Change to overall pain by the Visual Analogue Scale (VAS) after ITN stimulation 
 
10.2 Secondary Outcome Measures: 
 
 Change to overall pain by the Visual Analogue Scale (VAS) after daily ITN stimulation 
over 45-day period. 
 Change to overall pain by the Visual Analogue Scale (VAS) after daily ITN stimulation 
over 90-day period. 
 Change in quality of life as measured daily with OPAS and IDEEL  
 Safety 
 Tolerability 
 Change in response to hypertonic solution  
 Change in response to proparacaine challenge test  
 Change in the intraocular pressure (IOP) measured in each visit. 
 Reduction on other concomitant pain therapy 
 
 
10.3 Sample Size Determination: 
 
There is no existing systematic epidemiological study regarding the neuropathic corneal pain and 
there are no studies available to determine the population sample needed to detect differences 
between patients before and after the neuro stimulation for neuropathic corneal pain. However, 
based on a recent preliminary observations in 5 patients with concurrent NCP and dry eye 
disease, and the decrease in pain levels immediately after the use of ITN, we would achieve 80% 
power with an alpha error of 0.05 for pain scale intensity of 1-10, and assumption of 50% 
decrease in pain levels, for a sample size of 25 patients. The enrollment of 30 patients with NCP 
would compensate for potential dropouts. 
 
 
10.4 Analysis Population  
N/A 
 
10.5   Effectiveness Analysis  
 
Effectiveness will be assessed through pain and quality of life questionnaires (VAS/ OPAS/ 
IDEEL)   Questionnaires regarding changes or reduction in the current systemic medications will 
be applied and used as a clinical effective parameter. 
 
10.6   Safety Analysis 
 
The primary safety variable monitored will be the occurrence of adverse events. The severity of 
each adverse event observed will be evaluated as serious or not serious as defined by the Tufts 

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HSC and the occurrence will be evaluated as expected or unexpected. The relationship of the 
event to the study medication will be assessed by the investigator as possibly, probably, or 
definitely related. Safety variables will be evaluated at screening and at all study visits. If 
adverse events occur, the first concern will be the safety of the study participants. Any serious 
adverse event occurring during the study period will be immediately reported to Tufts IRB.  
Directed questioning will be done to assess tolerability. Additional steps taken to assess safety 
will be followed as outlined in section 8.1 of this SUPP M form.  
 
 
10.7   Interim Analysis  
N/A 
 
 

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11. DATA AND SAFETY MONITORING 
__________________________________________________________________ 
 
 
11.1   Data and Safety Monitoring Plan 
  
The PI, research fellows, research coordinators, and technicians involved with this protocol will 
be required to read the protocol, participate in a group meeting to discuss roles before the 
protocol is approved, and participate in weekly clinical research meetings. The pharmacy and the 
clinical fellows on the protocol will be required to read the protocol and separate meetings will 
be created to discuss roles as they relate to the protocol. 
 
A copy of the approved protocol and study related materials will be placed on a shared network 
drive accessible to authorized research staff involved in this study and on IRBnet.org. 
The primary safety variable monitored will be the occurrence of adverse events. The severity of 
each adverse event observed will be evaluated as outlined in section 10.6 by the treating 
investigator. The PI will be made aware of all AEs within one week. The ocular surface exam 
and IVCM imaging will only be performed by a research technician, fellow, or investigator to 
ensure adherence to the required tests and accurate assessments.  
 
The study coordinator will be responsible for monitoring each visit to ensure that the procedures 
are performed as outlined in the protocol and documented appropriately. 
 
Raw data collected for this study will be entered into a master database by the study coordinator, 
research technician, or fellow and uploaded for access to the principal investigator and all 
authorized research staff members on the U-Drive of password-protected computers located in 
the Cornea Research Department.  
 
 
 
 

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12. DATA HANDLING, RECORD-KEEPING AND MONITORING 
__________________________________________________________________ 
 
 
12.1   Data Recording, Record-Keeping and Monitoring  
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical study.  
The Investigator will review, approve and sign/date each completed CRF; the Investigator’s 
signature serving as attestation of the responsibility for ensuring that all clinical data entered on 
the CRF are complete, accurate and authentic.   
 
The LMR will be considered Source Data and will contain the clinical findings and observations, 
and other information collected during the visit. Subject consents will be maintained within the 
Department of Ophthalmology Clinical Research Office.  
 
All data will be stored on in the G-drive located on encrypted, password protected computers in 
the Cornea Research Department. Only the PI and researchers specific to this study who have 
been granted access to the data by the PI will be able to view the data in the TUFTS network 
protected folder. When data is sent out to be analyzed the data will be de-identified. The data 
will contain subject identification numbers, which are linked to identifiers on a separately 
secured spreadsheet. The data will be coded by assigning each participant a subject identification 
number and removing any identifiable information. The code will be secured by the PI and Study 
Coordinator in in the U-drive located on encrypted, password protected computers in the Cornea 
Research Department. The code that links information that can identify the participant to the data 
collected for this research will be kept separate from their health information, which will be 
destroyed once this study is complete and the manuscript has been published. 
 
Study data are boxed and logged when the study is terminated and housed in on-site locked room 
until the 7 year requirement is met, and then transferred to off-site storage. 
 
 
 

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13. STUDY DISCONTINUATION CRITERIA 
__________________________________________________________________ 
 
 
13.1   Discontinuation of Individual Research Subjects 
 
Please see sections 9.3. 
 
13.2   Investigator Discontinuation of the Clinical Research Study 
 
 
 
 

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References:  
 
1. Goyal S, Hamrah P. Understanding neuropathic corneal pain--gaps and current 
therapeutic approaches. Semin Ophthalmol. 2016;31:59-70. 
 
2. Theophanous C, Jacobs DS, Hamrah P. Corneal Neuralgia after LASIK. Optom Vis Sci. 
2015;92:e233-40. 
 
3. Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II 
pathophysiology report. Ocul Surf. 2017;15:438-510. 
 
4. Al-Aqaba MA, Fares U, Suleman H, Lowe J, Dua HS. Architecture and distribution of 
human corneal nerves. Br J Ophthalmol. 2010;94:784-9. 
 
5. Gallar J, Pozo MA, Tuckett RP, Belmonte C. Response of sensory units with 
unmyelinated fibres to mechanical, thermal and chemical stimulation of the cat's cornea. 
J Physiol. 1993;468:609-22. 
 
6. Chen X, Belmonte C, Rang HP. Capsaicin and carbon dioxide act by distinct mechanisms 
on sensory nerve terminals in the cat cornea. Pain. 1997;70:23-9. 
 
7. Moulton EA, Becerra L, Rosenthal P, Borsook D. An approach to localizing corneal pain 
representation in human primary somatosensory cortex. PLoS One. 2012;7:e44643. 
 
8. Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol. 2016;100:128-34. 
 
9. Rosenthal P, Borsook D. The corneal pain system. Part I: the missing piece of the dry eye 
puzzle. Ocul Surf. 2012;10:2-14. 
 
10. Goroszeniuk T, Pang D. Peripheral neuromodulation: a review. Curr Pain Headache Rep. 
2014;18:412. 
 
11. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971-9. 
 
12. Wall PD. The gate control theory of pain mechanisms. A re-examination and re-
statement. Brain. 1978;101:1-18. 
 
13. Friedman NJ, Butron K, Robledo N, Loudin J, Baba SN, Chayet A. A nonrandomized, 
open-label study to evaluate the effect of nasal stimulation on tear production in subjects 
with dry eye disease. Clin Ophthalmol. 2016;10:795-804. 
 
 
 
 
 
 

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Appendix I: Ocular Surface Disease Index (OSDI) 
Have you experienced any of the following during the last week: 
 
 
 
 
 
 
 
Have problems with your eyes limited you in performing any of the following during the 
last week: 
 
 
 
 
 
 
Have your eyes felt uncomfortable in any of the following situations during the last week: 
 
 
 
 
 
              
Total score for answers 1 to 12:    ____         
 
Total number of questions answered:    ____ 
 
(Do not include questions answered N/A)  
 
                                                                        
 OSDI = (sum of scores) x 25/(# of questions answered):     ____ 

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Appendix II: Cornea Fluorescein Staining  
 
Fluorescein 
instillation: 
Fluorescein strip wetted with buffered saline. Drop instilled on inferior palpebral conjunctiva. 
The participant is asked to blink several times. 
 
Staining:  
5 corneal regions (shown below) will be graded with a staining scale of 0-3. The “total scores” of 
the cornea and each region will be measured. 
 
 
 

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Appendix III:  Ocular Pain Assessment Scale (OPAS) questionnaire  
 
  

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Appendix IV:  Visual Analogue Scale questionnaire  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix V:  IDEEL QoL questionnaire  
  
 
Daily Activities 
 
 The following is a list of day-to-day activities that you may or may not have participated in 
OVER THE LAST TWO WEEKS.  
 If you participated in the activity, please choose how often you were limited in or stopped 
doing the activity BECAUSE OF YOUR DRY EYES.  
 Choose ‘I did not perform this activity due to reasons OTHER than dry eye’ if you did not 
take part in the activity for reasons other than your dry eyes.   
 Please choose only one box per question. 
 
 
 
OVER THE LAST TWO WEEKS I 
was limited BECAUSE OF MY DRY 
EYES: 
 
OVER THE LAST TWO 
WEEKS, how limited were 
you in doing the following 
activities 
BECAUSE 
OF 
YOUR DRY EYES? 
I did not 
do 
this 
activity for 
reasons 
OTHER 
than 
my 
dry 
eyes/Not 
applicable 
(5) 
None 
of the 
time 
(5) 
A little 
of 
the 
time 
(4) 
Some 
of the 
time 
(3) 
Most 
of the 
time 
(2) 
All of 
the 
time 
(1) 
I can no 
longer 
do this 
activity 
due to 
my dry 
eyes 
(0) 
1. 
Doing close work in the 
morning or afternoon 
(such 
as 
crossword 
puzzles, 
reading, 
looking at a computer, 
and/or sewing) 
 
 
 
 
 
 
 
2. 
Doing close work in the 
evening or at night 
 
 
 
 
 
 
 
3. 
Driving 
 
 
 
 
 
 
 
4. 
Being 
around 
and/or 
using scented products 
(such as cologne or 
hairspray) 
 
 
 
 
 
 
 
5. 
Working on a computer 
 
 
 
 
 
 
 
6. 
Going somewhere where 
there is tobacco smoke  
 
 
 
 
 
 

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OVER THE LAST TWO WEEKS I 
was limited BECAUSE OF MY DRY 
EYES: 
 
OVER THE LAST TWO 
WEEKS, how limited were 
you in doing the following 
activities 
BECAUSE 
OF 
YOUR DRY EYES? 
I did not 
do 
this 
activity for 
reasons 
OTHER 
than 
my 
dry 
eyes/Not 
applicable 
(5) 
None 
of the 
time 
(5) 
A little 
of 
the 
time 
(4) 
Some 
of the 
time 
(3) 
Most 
of the 
time 
(2) 
All of 
the 
time 
(1) 
I can no 
longer 
do this 
activity 
due to 
my dry 
eyes 
(0) 
or 
being 
around 
someone who smokes 
7. 
Wearing contact lenses 
 
 
 
 
 
 
 
8. 
Wearing make-up near 
or on my eyes 
 
 
 
 
 
 
 
9. 
Flying on an airplane 
 
 
 
 
 
 
 
 
 
Feelings 
 
The following questions ask about how dry eye affected your mood and social life OVER THE 
LAST TWO WEEKS.  Please choose how often you experienced each feeling BECAUSE OF 
YOUR DRY EYES.  Please choose only one box per question. 
 
OVER THE LAST TWO WEEKS, how often 
do you have each of the following feelings 
BECAUSE OF YOUR DRY EYES? 
OVER THE LAST TWO WEEKS, I 
experienced this feeling BECAUSE OF MY 
DRY EYES: 
None 
of the 
time 
(4) 
A little 
of the 
time 
(3)  
Some 
of the 
time 
(2) 
Most 
of the 
time 
(1) 
All of 
the 
time 
(0) 

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OVER THE LAST TWO WEEKS, how often 
do you have each of the following feelings 
BECAUSE OF YOUR DRY EYES? 
OVER THE LAST TWO WEEKS, I 
experienced this feeling BECAUSE OF MY 
DRY EYES: 
None 
of the 
time 
(4) 
A little 
of the 
time 
(3)  
Some 
of the 
time 
(2) 
Most 
of the 
time 
(1) 
All of 
the 
time 
(0) 
10. Irritability 
 
 
 
 
 
11. Impatience 
 
 
 
 
 
12. Feeling sad 
 
 
 
 
 
13. Worry that my dry eyes will get worse 
 
 
 
 
 
14. Feeling annoyed 
 
 
 
 
 
15. Feeling like my eyes do not look nice 
 
 
 
 
 
16. Feeling like I have to make adjustments to 
my life 
 
 
 
 
 
17. Feeling different from other people because 
of my dry eyes 
 
 
 
 
 
18. Feeling like I am always aware of my eyes 
 
 
 
 
 
19. Feeling older than I really am 
 
 
 
 
 
20. Feeling like people look at me and think I 
am fine when I’m not 
 
 
 
 
 
21. Feeling like there is nothing I can do for my 
dry eyes 
 
 
 
 
 
 
 
 
Work 
 
 
22. Are you currently working?  
 Yes 
If “Yes,” please read the instructions below. 
 No 
 

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The following questions ask about how often your dry eyes affected your work life OVER THE 
LAST TWO WEEKS.  Please choose how often you experienced the following situations at 
work BECAUSE OF YOUR DRY EYES.  Please choose only one box per question. 
 
 
OVER THE LAST TWO WEEKS I 
experienced the following situation at 
work BECAUSE OF MY DRY EYES: 
OVER THE LAST TWO WEEKS, how often did you 
experience the following situations at work BECAUSE 
OF YOUR DRY EYES? 
None 
of the 
time 
(4) 
A 
little 
of the 
time 
(3) 
Some 
of the 
time 
(2) 
Most 
of the 
time 
(1) 
All 
of 
the 
time 
(0) 
23. Feeling distracted  
 
 
 
 
 
24. Feeling like I couldn’t concentrate 
 
 
 
 
 
25. Having to take a break from work 
 
 
 
 
 
26. Having to change the way I work (such as the way I 
read, look at a computer, or work outside) 
 
 
 
 
 
27. Having to change my work environment (such as 
how close I am to an air conditioning or heating 
vent) 
 
 
 
 
 
 
 
 
Thank you for finishing this questionnaire. 
Please make sure that you answered every question. 
 
 
 
 

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Appendix VI: Ocular Tolerability and Compliance Questionnaire 
After you used the TrueTear® neurostimulation, how intensely have you 
experienced the following symptoms? 
Itching 
   Right Eye:     
None 
Trace Mild 
Moderate Severe 
 
     Left Eye: 
None    Trace   Mild      Moderate   Severe 
 
Burning Sensation 
   Right Eye:       
None 
Trace Mild 
Moderate Severe 
 
     Left Eye: 
None    Trace   Mild      Moderate   Severe 
 
Foreign Body Sensation 
   Right Eye:       
None 
Trace Mild 
Moderate Severe 
 
     Left Eye: 
None    Trace   Mild      Moderate   Severe 
 
Have you experienced any other symptoms after undergoing the study 
tests? 
YES 
 
NO 
 
If yes, which one(s)_________________________________________________ 
__________________________________________________________________ 
 
 
 

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Appendix VII: Diary Recording (Sample Pages):  
(Page 1):  
(may be replicated for each ITN use) 
 
Date:  
 
 
 
Time:  
 
1. Before ITN use: 
Discomfort 
 
 
Pain 
 
 
Photosensitivity/ 
Photoallodynia 
 
 
 
 
 
 
 
 
 
2. After ITN use: 
a. Discomfort   
after ____ mins of use 
 
Pain  
 
 
 
after ____ mins of use 
 
Photosensitivity/ 
Photoallodynia 
 
 
 
after ____ mins of use
 
 
 
3. Duration of ITN use needed:______ minutes 
4. Number of times ITN use was needed/day: __________ 
5. Duration of symptom-free period after ITN: _________ 
 
 
 
 
 

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(Page 2)  
(to be filled out for each day of the study) 
 
Date: