Efficacy of Locally Delivered Allogeneic Mesenchymal Stromal Cells

Study Overview
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Brief Summary
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The proposed Conventional Cohort Expansion Study involves the use of Mesenchymal Stromal Cells (MSCs) are derived from the bone marrow. We previously studied the safety of subconjunctival injection of allogeneic bone marrow-derived MSCs in patients with nonhealing epitheliopathy (IRB Protocol 2020-0334). In the present study, we want to study the efficacy of this treatment on chronic epitheliopathies.

Detailed Description
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The Efficacy of Locally Delivered Allogeneic Mesenchymal Stem Cells for Promoting Corneal Repair Study otherwise known as the MSC Study, is designed to assess the safety of allogeneic bone marrow-derived MSC secreted factor on the ocular surface via subconjunctival injection of MSC, and also obtain a preliminary observation on the following: Epithelial barrier integrity and/or wound closure. Development of Scarring. Final Visual Acuity. The objective is to improve clinical outcomes in significant non-healing corneal wounds. To achieve these goals, the MSC Study will include a Phase II efficacy study.

Official Title
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Efficacy of Locally Delivered Allogeneic Mesenchymal Stem Cells for Promoting Corneal Repair

Conditions
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Corneal Ulcer

Intervention / Treatment
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* Biological: Mesenchymal Stromal Cells
* Other: Control Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Visual Acuity: Best corrected distance visual acuity (BCDVA) score ≤ 75 ETDRS letters, (≥ 0.2 LogMAR, ≤ 20/32 Snellen or ≤ 0.625 decimal fraction) in the affected eye. Ocular Health: Patients with non-resolving corneal epitheliopathy or epithelial defect after two or more weeks of standard non-surgical treatments (e.g., preservative-free artificial tears, gels or ointments; discontinuation of preserved topical drops; anti-inflammatory therapy, soft bandage contact lens). No objective clinical evidence of improvement in the last 2 weeks (≤50% reduction in fluorescein staining or ≤50% reduction in longest diameter of the epithelial defect). If both eyes have chronic epithelial disease, the eye with the worse epithelial disease will be treated. Evidence of impaired epithelial barrier manifested by fluorescein staining of the epithelium with a score 10 or higher by National Eye Institute grading. Patients with stage 1 (no epithelial defect), stage 2 (persistent epithelial defect, PED; without stromal loss) or stage 3 (corneal ulcer; with stromal loss) neurotrophic keratopathy25-27 limited to ≤80% corneal diameter. Study Procedures: Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or legal representatives must have been approved by the IRB for the current study. Patients must have the ability and willingness to comply with study procedures. Exclusion Criteria: Visual Acuity: Best-corrected distance visual acuity (BCDVA) score better than 75 ETDRS letters, or 0.2 LogMAR, or 20/32 Snellen or 0.625 decimal fraction in the affected eye Ocular Health: Ocular drug toxicity less than two weeks ago Any active ocular infection (bacterial, viral, fungal or protozoal) or active ocular inflammation in the affected eye. History of any ocular surgery (including laser or refractive surgical procedures) in the affected eye within the three months before study enrollment. (An exception to the preceding statement will be allowed if the ocular surgery is considered to be the cause of the PED. Ocular surgery in the affected eye will not be allowed during the study treatment period and elective ocular surgery procedures should not be planned during the duration of the follow-up period unless the patient will be involved in corneal thinning of more than 1/3 corneal stroma, corneal melting or perforation. Prior surgical procedure(s) for the treatment of a chronic corneal epitheliopathy (e.g., complete tarsorrhaphy, conjunctival flap, etc.) in the affected eye with the exception of amniotic membrane transplantation. Patients previously treated with amniotic membrane transplantation may only be enrolled two weeks after the membrane has disappeared within the area of the chronic corneal epitheliopathy or corneal ulcer or at least six weeks after the date of the amniotic membrane transplantation procedure. Patients previously treated with Botox (botulinum toxin) injections used to induce pharmacologic blepharoptosis are eligible for enrollment only if the last injection was given at least 90 days prior to enrollment in the study. Chronic corneal epitheliopathy in the background of endothelial decompensation that needs corneal graft Anticipated need for punctual occlusion during the study treatment period. Patients with punctual occlusion or punctual plugs inserted prior to the study are eligible for enrollment provided that the punctual occlusion is maintained during the study. Evidence of corneal ulceration involving the posterior third of the corneal stroma, corneal melting or perforation in the affected eye. Presence or history of any ocular or systemic disorder or condition that might hinder the efficacy of the study treatment or its evaluation, could possibly interfere with the interpretation of study results, or could be judged by the investigator to be incompatible with the study visit schedule or conduct (e.g., progressive or degenerative corneal or retinal conditions, uveitis, optic neuritis, poorly controlled diabetes, autoimmune disease, systemic infection, neoplastic diseases). Patients with uncontrolled eyelid abnormality that preclude appropriate eyelid closure or including eyelash abnormality Study Procedures: Known hypersensitivity to one of the components of the study or procedural medications (e.g., fluorescein). History of drug, medication or alcohol abuse or addiction. Use of any investigational agent within 4 weeks of screening visit. Participation in another clinical study at the same time as the present study. Participants who are pregnant at the time of study enrollment will be excluded; pregnancy is identified according to the patient's self-report /positive βhCG

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Medium dose of allogenic MSC drops<br>Dose of allogeneic MSC subconjunctival injection will be assigned 3,000,000 cells/150 µL. | Biological: Mesenchymal Stromal Cells<br>* Subconjunctival Injection of Allogeneic Mesenchymal Stromal Cellsmasked clinical trial, patients with non-resolving corneal epithelial disease (i.e., refractory to standard treatments for at least two weeks) will receive a single subconjunctival injection of bone marrow-derived allogeneic MSCs or vehicle (CS5 freezing media, BioLife Solutions Inc, Bothell, WA, USA), with continued follow-up for up to 90 days.<br>|
| Sham Comparator: Control Group<br>For the control group, 50 µL of the freezing media (vehicle) will be injected. | Other: Control Solution<br>* For the control group, 150 µL of injectable normal saline (0.9% NaCl). will be injected.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of Corneal Epithelial Barrier and/or Integrity (Efficacy Rate) | The proportion of patients with improved epithelial barrier and/or integrity from baseline to DAY 28 as determined by the investigator on slit lamp examination: Improved epithelial barrier, defined as a 50 % improvement in corneal fluorescein staining score Improved epithelial integrity, defined as a healed epithelial defect | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Acuity | Percent change in best-corrected distance visual acuity from baseline to DAY 90, as measured using standard ETDRS protocols | Baseline, Days 1-7, 28, 60, 90 | 
| Corneal staining and NEI grading | Grading of fluorescein staining of the cornea | Baseline, Days 1-7, 28, 60, 90 | 
| Ocular Surface Parameters | Changes in tear breakup time (TBUT), ocular surface disease index (OSDI), Lissamine green staining, and anesthetic Schirmer's test from baseline to DAY 28 and DAY 90 | Baseline, Day 28, 90 | 
| Corneal Epithelial Thickness | Percent change in corneal epithelial thickness from baseline to DAY 28 and DAY 90, as measured by anterior segment OCT (AS-OCT) | Day 28, 90 | 
| Patient Symptoms | Changes in ocular discomfort visual analog scale (VAS) 0 - 100, where 0 is no discomfort and 100 the worst discomfort, from baseline to DAY 90 | Baseline, Days 1-7, 28, 60, 90 | 
| Time to epithelial healing | Time of improvement of epitheliopathy | Baseline, Days 1-7, 28, 60, 90 | 
| Corneal Scar | Change in the size of corneal scar (if present) from baseline to DAY 90, as documented by slit lamp photographs | Baseline, Days 1-7, 28, 60, 90 | 
| Corneal Neo-vascularization | Change in corneal vascularization on slit lamp photographs from baseline to DAY 90 | Baseline, Days 1-7, 28, 60, 90 | 
| Conjunctival injection | Change in conjunctival injection on slit lamp examination from baseline to DAY 90 | Baseline, Days 1-7, 28, 60, 90 |