Evaluation of the Clinical Efficacy and Mechanisms of Cord Plasma Eye Drops in the Treatment of Neuropathic Corneal Pain

The goal of this clinical trial is to investigate the efficacy and work of action of cord plasma eye drops in the treatment of neuropathic corneal pain (NCP). The main question it aims to answer if the cord plasma eye drops are effective for the treatment of NCP through its neurotrophic and anti-neuroinflammatory effects.

Study Overview

• Status: Recruiting
• Conditions: Neuropathic Pain; Corneal Disease
• Intervention / Treatment: Drug: Cord plasma eye drops

Detailed Description

Neuropathic corneal pain (NCP) is characterized by dysfunctional corneal nerves and ocular symptoms including pain, discomfort, burning, stinging, allodynia, and photophobia, are typically not relieved by conventional dry eye treatment due to its neurobiological nature. NCP can be associated with systemic diseases, such as diabetes mellitus and trigeminal neuralgia, or various ocular conditions such as severe dry eye disease, herpes simplex keratitis, or post-refractive surgery. The incidence of NCP is approximately 11-13% after refractive surgery (unpublished data), and it is likely to increase with the growing prevalence of dry eye and diabetes mellitus, as well as the growing popularity of ocular surgery. Moreover, the symptoms of NCP can greatly impact the quality of life and can cause a significant psychological and economic burden. It is often refractory to conventional treatments, leading to a significant impact on patients' quality of life and present as a challenge for clinicians seeking effective treatment strategies. The limited effectiveness of existing therapies for NCP has prompted the investigation of novel treatment options, including blood-derived eye drops.

Blood-derived eye drops, including serum-derived and plasma-derived eye drops, have been employed in a variety of clinical applications in ocular surface diseases because of their advantageous qualities and ability to enhance the ocular surface. Blood-derived eye drops can be prepared either from patients' own blood, such as autologous serum tears (AST) and Platelet-rich Plasma, or from allogeneic donors such as Umbilical Cord blood serum. A variety of bioactive compounds packed in blood-derived eye drops have equipped them with neuroprotective and regenerative properties that aid in corneal repair and nerve regeneration. Several mechanisms, including neuroprotection, anti-inflammatory effects, control of neuronal sensitization, and promotion of corneal epithelial repair, have been shown.

The potential efficacy of blood-derived eye drops on NCP has previously been studied. Aggarwal et al. have found that AST treatment reduced NCP patients' symptoms and enhanced the recovery of corneal nerve morphology. AST has also been reported to be beneficial for patients with photoallodynia in NCP. With the treatment with 20% AST, patients' allodynia and photoallodynia symptoms significantly improved within 3.6 months. Moreover, using autologous serum has been shown to reduce the appearance of neuromas and sub-basal corneal nerve beading. Additionally, serum tears have been shown to improve corneal nerve total length and number, as well as to reduce neural reflectivity and nerve tortuosity. Aggarwal et al. further found that the quantity of corneal nerve regeneration following treatment with AST correlated with the improvement in patients' symptoms of NCP. Another study investigated the neurotrophic potential of human platelet lysate (HPL) for corneal nerve regeneration in rat models. HPL has significantly higher concentrations of neurotrophic factors compared with human peripheral serum (HPS), and it showed corneal neurotrophic abilities both in vitro and in vivo. Taken together, blood-derived eye drops provide growth factors and cytokines that support corneal nerve regeneration, suppress ocular surface inflammation, and modulate the pain signaling pathways. However, the detailed mechanisms have not been investigated yet. Studies on the clinical efficacy and molecular profiles of the use of cord plasma eye drops in the treatment of NCP are also lacking.

SNEC has collaborated with Singapore Cord Blood Bank to provide cord blood plasma service, and cord blood plasma eye drops have been used as standard clinical care for patients with ocular surface diseases, severe dry eye, and NCP in SNEC. In the pilot study, the size of corneal neuromas has been found to be decreased after 3-month cord plasma eye drops treatment in patients with NCP (please find section 5 for preliminary data). The present proposal aim to evaluate the clinical efficacy and mechanisms of cord plasma eye drops in the treatment of NCP.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yu-Chi Liu, PhD; Phone Number: 65 65767493; Email: liu.yu.chi@snec.com.sg

Study Locations

• Singapore
  • Singapore
    • Singapore, Singapore, Singapore, 169856
      • Recruiting
      • Singapore Eye Research Institute
      • Contact: Yu-Chi Liu, PhD; Phone Number: 65 65767493; Email: liu.yu.chi@snec.com.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Persistent ocular pain or pain-like symptoms, including burning sensation, allodynia, photoallodynia, stinging, hyperalgesia, throbbing, shooting, sharp, cramping, gnawing, or a feeling of electric shock, with a minimum score of 30% for more than 3 questions in the OPAS questionnaire (see below section for OPAS questionnaire), for at least 3 months;
2. Presence of corneal nerve abnormalities, including microneuromas, beading, nerve tortuosity, decreased in corneal nerve fiber density (CNFD) or corneal nerve fiber length (CNFL), on IVCM images;
3. Minimal or no ocular surface fluorescein staining, with the National Eye Institute (NEI) and ocular surface Oxford score <2;
4. Patients who will receive cord plasma eye drops treatment

Exclusion Criteria:

1. Presence of active ocular surface diseases, such as active infective keratitis, the presence of epithelial defect or any other conditions that may cause nociceptive pain
2. Active anterior or posterior blepharitis;
3. Presence of concomitant ocular diseases that may cause ocular pain, such as uveitis or other ocular inflammatory diseases;
4. Concurrent treatment with immunosuppressants, such as topical cyclosporin or steroid eye drops
5. Concurrent use of oral Nonsteroidal anti-inflammatory drugs (NSAID) or other medications that may affect the pain scores

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with NCP; Patients who have been advised and scheduled to receive cord plasma eye drops treatment for their NCP will be recruited. The NCP will be diagnosed based on the following criteria.	Drug: Cord plasma eye drops; SNEC has collaborated with Singapore Cord Blood Bank to provide cord blood plasma service, and cord blood plasma eye drops have been used as standard clinical care for patients with ocular surface diseases, severe dry eye, and NCP in SNEC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain symptoms evaluated by Ocular Pain Assessment Survey (OPAS) questionnaire	Ocular pain will be assessed using the Ocular Pain Assessment Survey (OPAS) questionnaire. The Ocular Pain Assessment Survey (OPAS) is a 27-item questionnaire to evaluate the eye pain from 6 dimensions, including pain intensity for the last 24h, pain intensity for the last 2 weeks, non-eye pain intensity, quality of life, aggravating factors, associated factors and symptom relief. Each question was scored on a scale of 0-10 or 100%, with higher score representing worse pain.	3 months
Corneal nerve morphology assessment by in vivo confocal microscopy (IVCM)	IVCM (Heidelberg Retina Tomography III. Rostock Cornea Module, Heidelberg Engineering GmbH) will be used to examine the subbasal nerve plexus. The images will be analyzed using ACCMetrics software and get the quantitative nerve parameters.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tear neuromediator levels	Tear samples will be taken from the wetted Schirmer strips, and will be subjected to neuromediators analysis using enzyme-linked immunosorbent assay (ELISA): Substance P (pg/ml; 6x dilution), CGRP (pg/ml; 4x dilution), and NGF (pg/ml; 1.5x dilution), respectively (CGRP from Phoenix Pharmaceuticals, Runcorn, UK; Substance P and NGF from R&D Systems, Minneapolis, USA).	3 months
Ocular Surface Disease Index (OSDI) questionnaire to measure eye symptoms and the impact of quality of life.	The Ocular Surface Disease Index (OSDI), a 12-item questionnaire, will be also used to assess the symptoms of dry eye. The OSDI is a 12-item questionnaire that used to assess the eye symptoms and and their impact on vision-related quality of life.	3 months
Amount of tear production measured by Schirmer's I test	Schirmer's I test is a diagnostic method used to measure tear production by placing a standard 5 mm wide Test Strips inside the lower lid margin and assessing the amount of tear absorbed over 5 minutes.	3 months
Corneal sensitivity measurements assessed by Cochet-Bonnet esthesiometer	Corneal sensitivity measurements assess the responsiveness of the cornea to external stimuli using a contact Cochet-Bonnet esthesiometer, which employs a retractable nylon filament marked from 0 to 6 cm. The filament is progressively shortened in 0.5 cm increments until the participant perceives the stimulus. The maximum filament length that successfully triggers a response is recorded in centimeters as a measure of corneal sensitivity.	3 months
Tear film stability	Tear Break-up time (TBUT) will be measured by determining the time interval between a complete blink and the first appearance of a dry spot on the corneal surface, indicating tear film stability.	3 months
National Eye Institute (NEI) Score	The cornea will be divided into five regions, each scored ranging from 0 (no fluorescein staining) to 3 (severe fluorescein staining) according to the grading scheme. The total NEI score will range from 0 to 15.	3 months
Oxford scores	The staining intensity on the ocular surface will be assessed according to the Oxford score scheme: the staining pattern will be graded on a scale from 0 to 5, indicating the intensity from no staining to severe.	3 months
Corneal microneuromas morphology profiles	IVCM will be used to capture images of corneal microneuromas, which are characterized by irregularly shaped enlargements of terminal nerve endings with poorly defined margins and variable hyper-reflectivity. The images containing corneal microneuromas will be manually identified and the total area and perimeter will be quantified using Image J software.	3 months
Abundance of tear proteins assessed by quantitative proteomic analysis	Tear fluid samples will be collected by the strips from Schirmer's I test. Quantitative proteomic analysis technique will be used to measure and compare the abundance of proteins across different samples, providing insights into protein expression, functions, and molecular interactions.	3 months

Collaborators and Investigators

• Sponsor: Singapore Eye Research Institute

Publications and helpful links

General Publications

• Dieckmann G, Goyal S, Hamrah P. Neuropathic Corneal Pain: Approaches for Management. Ophthalmology. 2017 Nov;124(11S):S34-S47. doi: 10.1016/j.ophtha.2017.08.004.
• Gendrel D, Nardou M, Mouba JF, Gahouma D, Moussavou A, Boguikouma JB. [Hepatotoxicity of the combination of isoniazid-rifampicin in African children. Role of malnutrition and HB virus]. Arch Fr Pediatr. 1989 Nov;46(9):645-8. French.
• Aggarwal S, Colon C, Kheirkhah A, Hamrah P. Efficacy of autologous serum tears for treatment of neuropathic corneal pain. Ocul Surf. 2019 Jul;17(3):532-539. doi: 10.1016/j.jtos.2019.01.009. Epub 2019 Jan 24.
• Wong J, Govindasamy G, Prasath A, Hwang W, Ho A, Yeo S, Tong L. Allogeneic Umbilical Cord Plasma Eyedrops for the Treatment of Recalcitrant Dry Eye Disease Patients. J Clin Med. 2023 Oct 25;12(21):6750. doi: 10.3390/jcm12216750.
• Anam A, Liu C, Tong L, Liu YC. Blood-Derived Eye Drops for the Treatment of Corneal Neuropathic Pain. J Ocul Pharmacol Ther. 2024 Jun;40(5):281-292. doi: 10.1089/jop.2023.0155. Epub 2024 Apr 22.
• Norkett B. The role of nursing in marketing health care. Nurs Adm Q. 1985 Fall;10(1):85-9. doi: 10.1097/00006216-198510010-00009. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2023
• Primary Completion (Estimated): September 15, 2026
• Study Completion (Estimated): September 15, 2027

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 27, 2026
• First Posted (Actual): May 5, 2026

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Neuropathic corneal pain; Cord plasma eye drops; Blood-derived eye drops; Corneal nerves; Tear mediators
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Eye Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neuralgia; Corneal Diseases
• Other Study ID Numbers: 2023-2597

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No