Safety of Topical Mesenchymal Stromal Cell Secretome for Ocular Surface Disease

The "Safety of Topical Mesenchymal Stromal Cell Secretome for Ocular Surface Disease" study is designed to evaluate the safety and maximal tolerated dose (MTD) of topical MSC Secretome eye drops in patients with chronic ocular surface disease through a dose-escalation study under a 28-day topical application protocol, and also obtain a preliminary observation on the following:

1. Incidence of treatment emergent adverse events (TEAE) assessed at 28 days following treatment initiation
2. Proportion of patients with improved corneal epithelial barrier at 28 days compared to baseline
3. Final visual acuity, corneal epithelial thickness, corneal stromal haze, corneal sensation, and treatment tolerability

The objective is to determine the dose of MSC Secretome through a first-in-human study through a dose-escalation strategy targeting a toxicity rate of 33% or less.

• MSC Secretome Eye Drops (Biological): MSC Secretome eye drop will be dispensed.

Primary outcomes

• The Number of Participants In Each Dose Frequency Group With No Dose Limiting Toxicities Until Day 28 From The Start of Topical Allogeneic BM-MSC Secretome [Day 28]: Safety was defined with the absence of dose-limiting toxicity in the study eye until Day 28. Adverse events were defined using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5). Ocular adverse events included: Grade 2: vision loss ≤ 3 lines * increased corneal fluorescein staining by >50% * new conjunctivitis, scleritis, or uveitis 1-2+ cells in AC * increased corneal haze > 50%, stromal loss 10-30% Grade 3: loss of vision by > 3 lines up to 20/200 * new mild to moderate infectious/inflammatory keratitis with vision loss up to 20/200 * new corneal ulceration with > 30% stromal loss * new uveitis with 3-4+ cells in AC Grade 4: loss of vision by > 3 lines worse than 20/200 * new severe infectious/inflammatory keratitis * corneal perforation * Anaphylactic reaction, New SJS Note: Any grade 2 adverse event that lasted longer than 2 weeks or any adverse event of grades 3 or 4 was considered DLT. We also recorded all adverse events at each visit.
• Corneal Epithelial Integrity [Day 28]: The primary efficacy outcome measure was improved corneal epithelial barrier at 28 days compared to baseline - defined as ≥ 50% reduction in corneal fluorescein staining score using National Eye Institute (NEI) grading scale as measured by the investigators via slit lamp examination and assessment of slit lamp images.

Secondary outcomes

• Visual Acuity [Day 28]: Mean Change in best-corrected distance visual acuity (BCVA) in ETDRS letters on day 28 relative to baseline for each dose frequency group. The ETDRS letter score ranges from 0 to 100, where higher scores indicate better visual acuity.
• Change in Corneal Scarring / Haze Compared to Baseline [Day 28]: Corneal scarring/haze was assessed as the size of the hyperreflective area on AS OCT imaging (Cirrus 6000; HD cornea, a-scans) to assess the treatment effect on DAY #28 relative to baseline.
• Time to Improvement of Corneal Epithelial Barrier [Baseline, Days 7, 14, 28, 56, 90]: The time required for an improved epithelial barrier function was assessed at each visit throughout the trial.
• Tolerability of MSC Secretome Drops (Change in VAS Score on Day 28 Compared to Baseline) [Day 28]: Mean change in the patients' self-reported severity of discomfort and pain with visual analog scale (VAS; range 0 -100) on Day 28 compared to baseline for each dose frequency group. The higher numbers indicate more severe discomfort and pain.
• Change in Central Corneal Epithelial Thickness [Day 28]: Mean change in Central Corneal Epithelial Thickness on Day 28 from baseline.
• Durability of Corneal Epithelial Status Improvement [Days 42, 56, 90]: In patients with an improvement in corneal epithelial integrity defined as ≥50% improvement in corneal fluorescein staining with NEI scale on Day 28 from baseline, was the improvement maintained on Days 42, 56 and 90.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients 18 years of age or older
* Chronic corneal epithelial disease with fluorescein staining score ≥ 6 by NEI grading scale
* Reduced corneal sensation (≤ 4 cm measured by Cochet Bonnet esthesiometry) in at least one corneal quadrant
* A stable ocular surface with no objective clinical evidence of significant (> 50%) improvement/worsening of the epithelial disease in the last 30 days
* Epithelial disease refractory to conventional non-surgical treatments (e.g., preservative-free artificial tears, gels or ointments; discontinuation of preserved topical drops; anti-inflammatory therapy)

Exclusion Criteria:

* Any active or suspected ocular infection (bacterial, viral, fungal or protozoal).
* Evidence of corneal ulceration with stromal loss > 10%
* Presence of an epithelial defect ≥1.0 mm in the largest diameter in the affected eye
* Presence of any size epithelial defect that has been persistent for more than 30 days
* Patients unable to discontinue or intermittently remove therapeutic contact lens in the study eye (to apply drops) during the 4-week study period
* History of any ocular surgery (including laser or refractive surgical procedures) in the affected eye within the 3 months prior to study enrollment
* History of chemical injury within the last 6 months prior to study enrollment 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
* History of previous enrollment in the MSC Secretome Study at a lower dose
* Participation in another clinical study at the same time as the present study
* Participants who are pregnant at the time of study enrollment

Participant flow

Outcome results

• The Number of Participants In Each Dose Frequency Group With No Dose Limiting Toxicities Until Day 28 From The Start of Topical Allogeneic BM-MSC Secretome (Primary), Number, participants: Low Dose of Allogeneic MSC Drops 3; Medium Dose of Allogeneic MSC Drops 3; High Dose of Allogeneic MSC Drops 1
• Corneal Epithelial Integrity (Primary), Number, participants: Low Dose of Allogeneic MSC Drops 3; Medium Dose of Allogeneic MSC Drops 3; High Dose of Allogeneic MSC Drops 1
• Visual Acuity (Secondary), Mean, ETDRS Letter Scores: Low Dose of Allogeneic MSC Drops 15 +/- 5; Medium Dose of Allogeneic MSC Drops 12.7 +/- 10.8; High Dose of Allogeneic MSC Drops -10.7 +/- 13
• Change in Corneal Scarring / Haze Compared to Baseline (Secondary), Mean, (µm)²: Low Dose of Allogeneic MSC Drops 0 +/- 0; Medium Dose of Allogeneic MSC Drops 0 +/- 0; High Dose of Allogeneic MSC Drops 0 +/- 0
• Time to Improvement of Corneal Epithelial Barrier (Secondary), Number, participants: Low Dose of Allogeneic MSC Drops 0; Medium Dose of Allogeneic MSC Drops 0; High Dose of Allogeneic MSC Drops 0
• Tolerability of MSC Secretome Drops (Change in VAS Score on Day 28 Compared to Baseline) (Secondary), Mean, VAS Score: Low Dose of Allogeneic MSC Drops -7 +/- 11.3; Medium Dose of Allogeneic MSC Drops 13.3 +/- 32; High Dose of Allogeneic MSC Drops 4.7 +/- 31
• Change in Central Corneal Epithelial Thickness (Secondary), Mean, micrometers: Low Dose of Allogenic MSC Drops 7 +/- 8; Medium Dose of Allogenic MSC Drops -1.6 +/- 2.9; High Dose of Allogenic MSC Drops 6 +/- 0
• Durability of Corneal Epithelial Status Improvement (Secondary), Number, participants: Low Dose of Allogenic MSC Drops 0; Medium Dose of Allogenic MSC Drops 0; High Dose of Allogenic MSC Drops 0

Adverse events

Time frame: From first dose (Day 0) through Day 90 follow-up (90 days after start of treatment).

Other adverse events by term

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• Study Protocol and Statistical Analysis Plan (PDF, 2023-12-08)

• Ali R Djalilian, MD, Principal investigator, University of Illinois at Chicago
• Charlotte E Joslin, OD, PhD, Principal investigator, University of Illinois at Chicago
• Elmer Y Tu, MD, Principal investigator, University of Illinois at Chicago

NIH grants: 1UG3EY031809-01