Prospective Study to Validate the Imaging Biomarker for NCP (R33)

Study Overview
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Brief Summary
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The aim of this study is establish the reliability and clinical utility of microneuromas as identified via in vivo confocal microscopy as the diagnostic biomarker for NCP.

Detailed Description
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Dry Eye Disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities. Neuropathic corneal pain (NCP), an ocular and severe type of neuropathic pain describes patients with symptoms of ocular discomfort out of proportion with clinical signs. The lack of clinical signs observed by standard ophthalmic examination has resulted in underdiagnosis of NCP or misdiagnosis as dry eye disease. Thus, having a biomarker for NCP is critical to identify and treat these patients. No biomarker or clinical signs exists to identify NCP patients. Investigating corneal neurosensory abnormalities could help to diagnose NCP and potentially differentiate these patients from those with DED. In vivo confocal microscopy (IVCM) allows for real-time optical biopsies at a quasi-histological level, allowing for assessment of corneal nerves. IVCM non-invasive diagnostic imaging across NCP, DED, and healthy individuals will be analyzed to validate corneal microneuromas as a biomarker for NCP.

Official Title
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Prospective Study to Validate the Imaging Biomarker for Neuropathic Corneal Pain.

Conditions
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Dry Eye Syndromes, Corneal Disease

Intervention / Treatment
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* Other: In vivo confocal microscopy (IVCM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Subjects: 18 years of age or older Ability to consent Best corrected visual acuity of 20/40 or better in each eye Dry Eye Disease Group: Chief complaint is ocular surface discomfort or dry eye disease, but subject reports no ocular pain on OPAS questionnaire Symptoms lasting at least 3 months Presence of at least two of the following within the same eye: Anesthetized Schirmer score =/< 10mm Corneal staining of >3/15 based on NEI scale Tear break up time < 10 seconds Neuropathic Corneal Pain Group: Chief complain is ocular surface discomfort or dry eye disease Symptoms lasting at least 3 months All of the following in both eyes: Corneal staining of less than or equal to 3/15 based on NEI scale Tear break up time =/> 10 seconds Must have at least 25% peripheral pain Subject reported discomfort prior to drop response testing of at least 3 out of 10 Control Group: No symptoms of ocular surface discomfort or dry eye disease All of the following in both eyes Anesthetized Schirmer score > 10 mm Corneal staining of less than or equal to 3/15 based on NEI scale Tear break up time > 10 seconds The same sex and within 5 years of age of a patient within the NCP group. Exclusion Criteria: Pregnant or nursing Irregular corneal disease Ocular surgery in the past 3 months Ocular infection in the past 3 months Active ocular allergies Participation in a study that could potentially impact the IVCM in the opinion of the investigator Current use of corneal nerve regeneration therapy that has been on-going for 3 months or more. For NCP group only, patients for whom their pain and symptoms can be attributed to other causes in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Dry Eye Disease Group<br>Symptoms of ocular surface discomfort or dry eye disease for at least 3 months, supported by clinical exam findings. Reported quality of life is not effected by ocular pain. | Other: In vivo confocal microscopy (IVCM)<br>* In vivo confocal microscopy (IVCM) allows for visualization of the corneal structures at the cellular level, allowing for assessment of corneal nerves. With a magnification of 800 times, it makes it possible to detect and quantify changes in the epithelial layers and sub-basal nerve plexus.<br>|
| Other: Neuropathic Corneal Pain Group<br>Symptoms of ocular surface discomfort or pain for at least 3 months, that are reported to have a significant impact on quality of life and ability to perform daily activities. | Other: In vivo confocal microscopy (IVCM)<br>* In vivo confocal microscopy (IVCM) allows for visualization of the corneal structures at the cellular level, allowing for assessment of corneal nerves. With a magnification of 800 times, it makes it possible to detect and quantify changes in the epithelial layers and sub-basal nerve plexus.<br>|
| Other: Control Group<br>No symptoms of ocular surface discomfort or dry eye disease. | Other: In vivo confocal microscopy (IVCM)<br>* In vivo confocal microscopy (IVCM) allows for visualization of the corneal structures at the cellular level, allowing for assessment of corneal nerves. With a magnification of 800 times, it makes it possible to detect and quantify changes in the epithelial layers and sub-basal nerve plexus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of microneuromas as assessed by in vivo confocal microscopy (IVCM). | The obtained sequence of IVCM imaging scans of both eyes will be evaluated for findings of microneuromas; defined as either observed presence or absence of microneuroma | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-subject repeatability; Presence of the microneuroma biomarker in the same participant at 2 weeks | Confirmation of presence of microneuroma on IVCM at 2 weeks in participants with IVCM finding of microneruoma at Visit 1 | From Day 1 to 2 weeks | 
| Establish the reference interval for the microneuroma biomarker | Quantification of microneuromas as assessed by IVCM in each cohort (Normal vs. NCP vs. DED) | Day 1 | 
| Ocular Pain Assessment Survey (OPAS) questionnaire results correlation to microneuromas; OPAS reported quality of life score compared across the 3 cohorts. | Ocular Pain Assessment Survey (OPAS) questionnaire: 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. Higher scores indicate greater impact of ocular pain on quality of life dimensions. | Day 1 | 
| Hyperosmolar functional nerve tests in correlation to microneuromas; hyperosmolar functional nerve tests results compared cross cohorts | Using the Pain Visual Analogue Scale (VAS), Symptoms of ocular comfort and dryness at the time in question will be graded for each eye verbally on a scale of 0-10, where 0=excellent comfort, no dryness and 10=extremely uncomfortable, extremely dry. A single drop of hypertonic sodium chloride solution (Muro 128®, 5%) at room temperature will be instilled into each eye. After 20 seconds, participants will be asked to grade their ocular comfort and dryness symptoms as described in the VAS procedure again allowing assessment of changes in sensation due to the hyperosmolar drop and activation of the polymodal nociceptors | Day 1 | 
| Test the utility of already configured AI software to diagnose NCP patients | categorical variables of NCP and DED as diagnosed by the AI system and the classification of subjects into the NCP and DED groups based on inclusion criteria set by the study | Day 1 to 2 weeks |