Safety of Locally Delivered Allogeneic Mesenchymal Stromal Cells

Study Overview
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Brief Summary
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This study is a longitudinal assessment using a classic dose-escalation study design to assess the safety and maximal tolerated dose (MTD) of locally delivered allogeneic mesenchymal stromal cells (MSC) for promoting corneal repair. The study will be conducted at Illinois Eye and Ear Infirmary located at University of Illinois at Chicago. The study will use digital conjunctival and corneal photography and corneal Scheimpflug Imaging, densitometry, and pachymetry for assessment of safety and corneal wound healing.

Detailed Description
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The Safety 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 I dose-escalation safety study.

Official Title
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Safety of Locally Delivered Allogeneic Mesenchymal Stromal Cells for Promoting Corneal Repair

Conditions
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Cornea, Mesenchymal Stromal Cells, Safety, Corneal Defect

Intervention / Treatment
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* Biological: Allogeneic MSC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: • Patients 18 years of age or older 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 moderate to severe chronic corneal epithelial disease in the setting of neurotrophic keratitis, limbal stem cell deficiency, or inflammatory dry eye disease. Epithelial disease refractory to all applicable standard / FDA approved non-surgical treatments (e.g., preservative-free artificial tears, gels or ointments; discontinuation of preserved topical drops; anti-inflammatory therapy, and soft bandage contact lens). Evidence of impaired epithelial barrier manifested by fluorescein staining of the epithelium with a score 6 or higher by National Eye Institute grading. No objective clinical evidence of improvement since the last visit (≤50% reduction in fluorescein staining or ≤50% reduction in longest diameter of the epithelial defect). 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 keratopathy 28-30 limited to ≤80% corneal diameter. Stromal loss in corneal ulcers cannot exceed 50%. Etiology of all persistent epithelial defects and corneal ulcers will be neurotrophic in nature. Neurotrophic keratopathy may be due to previous trauma such as chemical and thermal burns, systemic diseases like diabetes, post-infectious keratitis such as herpetic disease, or cranial nerve V palsies such as surgery for trigeminal neuralgia. PED or corneal ulceration refractory to one or more conventional non-surgical treatments (e.g., preservative-free artificial tears, gels or ointments; discontinuation of preserved topical drops and medications that can decrease corneal sensitivity; therapeutic contact lenses). No objective clinical evidence of improvement in the PED or corneal ulceration within the week prior to study enrollment (e.g., ≤50% reduction in longest diameter in 1 week). Evidence of decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) within the area of the PED or corneal ulcer and outside of the area of the defect in at least one corneal quadrant. Exclusion Criteria: Visual Acuity: • Patients with severe vision loss in the affected eye with no potential for visual improvement in the opinion of the investigator as a result of the study treatment. Ocular Health: Any active ocular infection (bacterial, viral, fungal or protozoal) or active ocular inflammation not related to PED 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. Prior surgical procedure(s) for the treatment of a PED (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 PED 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. 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). Any need for or anticipated change in the dose of systemic medications known to impair the function of the trigeminal nerve (e.g., neuroleptics, antipsychotic and antihistamine drugs). These treatments are allowed during the study if initiated prior to 30 days before study enrollment provided they remain stable throughout the course of the study treatment periods. 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.

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A longitudinal assessment using a classic dose-escalation study design to assess the safety of locally delivered allogenic mesenchymal stromal cells for promoting corneal repair.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low dose of allogeneic MSC<br>Escalating doses of allogeneic MSC subconjunctival injection will be assigned 1,000,000 cells/50 µL at the low dose level. | Biological: Allogeneic MSC<br>* Subconjunctival Injection of Allogeneic Mesenchymal Stromal Cells<br>|
| Active Comparator: Medium dose of allogeneic MSC<br>Escalating doses of allogeneic MSC subconjunctival injection will be assigned 3,000,000 cells/150 µL at the medium dose level. | Biological: Allogeneic MSC<br>* Subconjunctival Injection of Allogeneic Mesenchymal Stromal Cells<br>|
| Active Comparator: High dose of allogeneic MSC<br>Escalating doses of allogeneic MSC subconjunctival injection will be assigned 6,000,000 cells total consisting of injection at 2 sites of 3,000,000 cells/150 µL each at the high dose level. | Biological: Allogeneic MSC<br>* Subconjunctival Injection of Allogeneic Mesenchymal Stromal Cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Outcome: Incidence of treatment emergent adverse events (TEAE) assessed at 28 days. | Slit lamp exam will assess the safety of the treatment via TEAE at 28 days (participants will receive continued monitoring through 90 days). TEAE will be defined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5) adverse event reference, and used to identify dose-limiting toxicity (DLT). The DLT will be defined as any non-corneal, ocular or systemic TEAE, with a Grade 2 toxicity without resolution after 14 days OR a Grade 3 toxicity, unless it can clearly be attributed to another cause. The DLT will be used to define the maximal tolerated dose (MTD). The MTD will be defined as the highest dose at which 0 to 1 of 6 patients experiences a dose-limiting toxicity (DLT). If a DLT occurs in 2 patients in a dosing cohort, then the MTD is considered exceeded and the dose will not be escalated. | Day #28 | 
| Primary Efficacy Outcome: Proportion of participants with improvement in epithelial defect or barrier integrity relative to baseline (based on fluorescein staining) | Presence or absence of epithelial defect and epithelial staining grade following treatment, as determined by fluorescein staining observed via slit lamp examination, and photo-documented with digital corneal photography. | Day #28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Efficacy Outcomes: Visual Acuity | Best-corrected distance visual acuity will be measured using standard e-ETDRS protocols. | Enrollment, Treatment, and Days #1, #7, #14, #28, #90 | 
| Secondary Efficacy Outcomes: Time to Completion of Corneal Epithelialization | Time to completion of corneal epithelialization will be assessed at each visit throughout the trial. Corneal epithelialization will be assessed as previously described. | Enrollment, Treatment, and Days #1, #7, #14, #28, #90 | 
| Secondary Efficacy Outcomes: Durability of the Corneal Epithelialization and Healing | Durability of the corneal epithelization and healing will be assessed as an outcome measure at DAY #28 and DAY #90. Participants with corneal epithelialization prior to DAY #28 will be assessed at each subsequent follow-up visit (e.g., DAYS #7, #14, #28) to assess persistence of the healing response. Corneal epithelialization will be assessed as previously described. | Enrollment, Treatment, and Days #1, #7, #14, #28, #90 | 
| Secondary Efficacy Outcomes: Corneal stromal haze | Corneal stromal haze will be measured from Scheimpflug imaging and anterior segment OCT images (using Image J software). The treatment effect on corneal haze on DAY #28 will be compared relative to baseline. | Enrollment and Days #7, #14, #28, #90 | 
| Secondary Efficacy Outcomes: Corneal epithelial thickness | Corneal epithelial thickness measured by anterior segment OCT imaging will assess the treatment effect on thickness on DAY #28 and compared relative to baseline. | Enrollment and Days #7, #14, #28, #90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesenchymal Stromal Cells, Corneal Defect