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

• ClinicalTrials.gov Identifier: NCT05653921
• Recruitment Status: Recruiting
• First Posted: December 16, 2022
• Last Update Posted: January 19, 2023
• Sponsor: Tufts Medical Center
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Tufts Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Dry Eye Syndromes; Corneal Disease	Diagnostic Test: In vivo confocal microscopy (IVCM)

Detailed Description:

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.

Study Design

• Study Type: Observational
• Estimated Enrollment: 438 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Prospective Study to Validate the Imaging Biomarker for Neuropathic Corneal Pain.
• Actual Study Start Date: December 16, 2022
• Estimated Primary Completion Date: October 31, 2024
• Estimated Study Completion Date: October 31, 2028

Groups and Cohorts

Group/Cohort	Intervention/treatment
Dry Eye Disease Group; 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.	Diagnostic Test: In vivo confocal microscopy (IVCM); 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.
Neuropathic Corneal Pain Group; 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.	Diagnostic Test: In vivo confocal microscopy (IVCM); 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.
Control Group; No symptoms of ocular surface discomfort or dry eye disease.	Diagnostic Test: In vivo confocal microscopy (IVCM); 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.

Outcome Measures

Primary Outcome Measures :

1. Presence of microneuromas as assessed by in vivo confocal microscopy (IVCM). [ Time Frame: Day 1 ]
   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

Secondary Outcome Measures :

1. Intra-subject repeatability; Presence of the microneuroma biomarker in the same participant at 2 weeks [ Time Frame: From Day 1 to 2 weeks ]
   Confirmation of presence of microneuroma on IVCM at 2 weeks in participants with IVCM finding of microneruoma at Visit 1
2. Establish the reference interval for the microneuroma biomarker [ Time Frame: Day 1 ]
   Quantification of microneuromas as assessed by IVCM in each cohort (Normal vs. NCP vs. DED)
3. Ocular Pain Assessment Survey (OPAS) questionnaire results correlation to microneuromas; OPAS reported quality of life score compared across the 3 cohorts. [ Time Frame: Day 1 ]
   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.
4. Hyperosmolar functional nerve tests in correlation to microneuromas; hyperosmolar functional nerve tests results compared cross cohorts [ Time Frame: Day 1 ]
   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
5. Test the utility of already configured AI software to diagnose NCP patients [ Time Frame: Day 1 to 2 weeks ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

We will not be limiting the inclusion of the NCP or DED groups for this study. We will be recruiting from two Cornea Clinics in diverse large cities of Boston and Philadelphia. Thus, the sample collected from this group is expected to be representative of the population for each of these groups. We will be limiting inclusion of the control group to those age and sex matched controls as described above. This will allow for the conclusions drawn from this study to be more applicable in clinical practice. Without an age and sex matched control group, one could attribute differences in IVCM to these two variables instead of the disease(s).

Criteria

Inclusion Criteria:

All Subjects:

1. 18 years of age or older
2. Ability to consent
3. Best corrected visual acuity of 20/40 or better in each eye

Dry Eye Disease Group:

1. Chief complaint is ocular surface discomfort or dry eye disease, but subject reports no ocular pain on OPAS questionnaire
2. Symptoms lasting at least 3 months

3. Presence of at least two of the following within the same eye:

   1. Anesthetized Schirmer score < 10mm
   2. Corneal staining of >3/15 based on NEI scale
   3. Tear break up time < 10 seconds

Neuropathic Corneal Pain Group:

1. Chief complain is ocular surface discomfort or dry eye disease
2. Symptoms lasting at least 3 months

3. All of the following in both eyes:

   1. Anesthetized Schirmer score > 10 mm
   2. Corneal staining of less than or equal to 3/15 based on NEI scale
   3. Tear break up time > 10 seconds

Control Group:

1. No symptoms of ocular surface discomfort or dry eye disease

2. All of the following in both eyes

   1. Anesthetized Schirmer score > 10 mm
   2. Corneal staining of less than or equal to 3/15 based on NEI scale
   3. Tear break up time > 10 seconds
3. The same sex and within 5 years of age of a patient within the NCP group.

Exclusion Criteria:

1. Pregnant or nursing
2. Irregular corneal disease
3. Ocular surgery in the past 3 months
4. Ocular infection in the past 3 months
5. Active ocular allergies
6. Participation in a study that could potentially impact the IVCM in the opinion of the investigator

Contacts and Locations

Contacts

Contact: Nancy Gee, MPH; 617-636-5489; ngee@tuftsmedicalcenter.org

Locations

United States, Massachusetts

Tufts Medical Center; Recruiting

Boston, Massachusetts, United States, 02111

Contact: Nancy Gee, MPH 617-636-5489 ngee@tuftsmedicalcenter.org

Principal Investigator: Pedram Hamrah, MD

United States, Pennsylvania

Scheie Eye Institute, University of Pennsylvania; Not yet recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Giacomina Massaro-Giordano, MD

Principal Investigator: Giacomina Massaro-Giordano, MD

Sponsors and Collaborators

Tufts Medical Center

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Pedram Hamrah, MD; Tufts Medical Center

More Information

Publications:

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Ferrari G, Nallasamy N, Downs H, Dana R, Oaklander AL. Corneal innervation as a window to peripheral neuropathies. Exp Eye Res. 2013 Aug;113:148-50. doi: 10.1016/j.exer.2013.05.016. Epub 2013 Jun 14. Erratum In: Exp Eye Res. 2016 Apr;145:473.

Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea. 2004 Nov;23(8):762-70. doi: 10.1097/01.ico.0000133997.07144.9e.

Sullivan BD, Crews LA, Messmer EM, Foulks GN, Nichols KK, Baenninger P, Geerling G, Figueiredo F, Lemp MA. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol. 2014 Mar;92(2):161-6. doi: 10.1111/aos.12012. Epub 2012 Dec 28.

Nichols KK, Bacharach J, Holland E, Kislan T, Shettle L, Lunacsek O, Lennert B, Burk C, Patel V. Impact of Dry Eye Disease on Work Productivity, and Patients' Satisfaction With Over-the-Counter Dry Eye Treatments. Invest Ophthalmol Vis Sci. 2016 Jun 1;57(7):2975-82. doi: 10.1167/iovs.16-19419.

Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, Lauria G. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008 Jul;131(Pt 7):1912-25. doi: 10.1093/brain/awn093. Epub 2008 Jun 4.

Classification of Chronic Pain, Part III: Pain Terms, A Current List with Definitions and Notes on Usage. Second ed. Seattle: IASP Press; 1994

Dieckmann G, Koseoglu N, Moein HR, Kataguiri P, Hamrah P. Epidemiological factors of neuropathic corneal pain. IASP: The 18th World Congress on Pain; 2018; Boston, MA.

Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols JJ, Tsubota K, Stapleton F. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017 Jul;15(3):276-283. doi: 10.1016/j.jtos.2017.05.008. Epub 2017 Jul 20.

Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea. 2011 Apr;30(4):379-87. doi: 10.1097/ICO.0b013e3181f7f363.

Lopez MJ, Jamali A, Dieckmann G, et al. Corneal Pain Has a Negative Impact on the Quality of Life of Patients with Neuropathic Corneal Pain. Investigative ophthalmology & visual science. 2018;59(9):138-138

Lopez MJ, Abbouda A, Pondelis N, et al. The Ocular Pain Assessment Survey and In Vivo Confocal Microscopy as Valuable Tools in the Diagnosis and Management of Patients with Corneal Neuropathic Pain. Investigative ophthalmology & visual science. 2017;58(8):1013-1013.

• Responsible Party: Tufts Medical Center
• ClinicalTrials.gov Identifier: NCT05653921
• Other Study ID Numbers: STUDY00003018; 4R33NS113341-02 ( U.S. NIH Grant/Contract )
• First Posted: December 16, 2022
• Last Update Posted: January 19, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Dry Eye Syndromes; Corneal Diseases; Lacrimal Apparatus Diseases; Eye Diseases