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

Dry Eye Syndromes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05653921
• Other study ID #: STUDY00003018
• Secondary ID: 4R33NS113341-02
• Status: Recruiting
• Start date: December 16, 2022
• Est. completion date: July 14, 2025

Study information

• Verified date: April 2024
• Source: Tufts Medical Center
• Contact: Nancy Gee, MPH
• Phone: 617-636-5489
• Email: ngee[@]tuftsmedicalcenter.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 438
• Est. completion date: July 14, 2025
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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. Corneal staining of less than or equal to 3/15 based on NEI scale

2. Tear break up time =/> 10 seconds

4. Must have at least 25% peripheral pain

5. Subject reported discomfort prior to drop response testing of at least 3 out of 10

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

7. Current use of corneal nerve regeneration therapy that has been on-going for 3 months or more.

8. For NCP group only, patients for whom their pain and symptoms can be attributed to other causes in the opinion of the investigator

Related Conditions & MeSH terms

• Corneal Disease
• Corneal Diseases
• Dry Eye Syndromes

Intervention

Other:
• 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.

Locations

Country	Name	City	State
United States	Tufts Medical Center	Boston	Massachusetts
United States	Scheie Eye Institute, University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Tufts Medical Center	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (12)

Bujang MA, Adnan TH. Requirements for Minimum Sample Size for Sensitivity and Specificity Analysis. J Clin Diagn Res. 2016 Oct;10(10):YE01-YE06. doi: 10.7860/JCDR/2016/18129.8744. Epub 2016 Oct 1. — View Citation

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

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. — View Citation

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. — View Citation

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.

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. — View Citation

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.

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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