Evaluation of Allogenic Mesenchymal Stem Cell (MSC) Injection Therapy for Refractory Graft-versus-Host Disease (GVHD) Unresponsive to Conventional Treatments

Official title

A Phase IIB Clinical Trial to Evaluate the Efficacy and Safety of Allogenic Mesenchymal Stem Cell (MSC) Injection Therapy for Refractory Graft-versus-Host Disease (GVHD) Unresponsive to Conventional Treatments

Overview

This Phase IIB, multicenter, double-blind, randomized, and uncontrolled clinical trial aims to assess the efficacy and safety of subconjunctival injection of Mesenchymal Stem Cells (MSCs) in patients with Graft-versus-Host Disease (GVHD) and severe ocular involvement (DYD-dry eye disease). The primary objective is to evaluate the clinically and statistically significant improvement in the signs and symptoms associated with the disease. Secondary objectives include: * Analyzing adverse events related to the subconjunctival injection of MSCs to confirm the safety of this treatment in patients with GVHD ocular involvement. * Identifying new biomarkers that can be used to objectively assess the progression of patients with GVHD and severe ocular involvement. * Studying the relationship between the expression of ocular surface-specific markers by MSCs and their clinical efficacy, as well as the variation in the expression of these markers in relation to cell preservation methods. Assessing the quality of life of patients treated with two doses of MSCs using the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire). \- Evaluating whether the cell dose impacts clinical improvement. The trial includes 30 patients, divided into two groups of 15, and focuses on the assessment of dry eye disease, with the treatment based on MSC administration to improve clinical outcomes and quality of life for the patients.

Interventions

• Drug Subconjuntival injection of expanded allogenic adult adipose tissue-derived mesenchymal stem cells (ASC
  Subconjunctival injection is a widely used technique in ophthalmology due to its effectiveness, minimal invasiveness, and ease of administration. In a subconjunctival injection the cells adult adipose tissue-derived mesenchimal cells are delivered into the subconjunctival space, the area between the conjunctiva and sclera.

Primary outcome measures

• Change in the integrity of the ocular surface [Time frame: six and twelve months from start of treatment]
• Change in tear production [Time frame: six and twelve months from start of treatment]
• Change in the degree of conjunctival hyperemia [Time frame: six and twelve months from start of treatment]
• Change in the parameters related to the Meibomian glands [Time frame: six and twelve months from start of treatment]
• Change in any of the findings in the central cornea [Time frame: six and twelve months from start of treatment]
• Severity of eye disease measured by WFPRS (Wong-Baker Faces Pain Rating Scale) [Time frame: six and twelve months from start of treatment]
• Severity of eye disease measured by Numerical Rating Scale (NRS) [Time frame: six and twelve months from start of treatment]
• Severity of eye disease measured by Modified Symptom Assessment in Dry Eye Questionnaire (mSIDEQ) [Time frame: six and twelve months from start of treatment]
• Severity of eye disease measured by Ocular Surface Disease Index (OSDI) [Time frame: six and twelve months from start of treatment]
• Severity of eye disease measured by CDES-Q (Contact Lens Dry Eye Symptom Questionnaire) [Time frame: six and twelve months from start of treatment]

Secondary outcome measures (4)

• Rate of adverse events related to the administration of subconjunctival ASC injection. [Time frame: Through study completion, an average of 1 year]
• Analysis of ocular marker expression in the administered ASCs [Time frame: When vials are thawed before treating the first patients with 6.25 mill and 12.5 mill ASC, 1 year afterwards and two years afterwards or altertatively, when vials are thawed to treat the last patient with 6.25 and 12.5 mill ASC.]
• Analysis of the presence and concentration of inflammation-related molecules in tear and serum samples [Time frame: Visit 2 (day 14 ± 7 after screening), 6 months, 12 months and when applicable, at premature withdrawal.]
• Search for new biomarkers that can be used to objectively evaluate the progression of patients affected by EICRc with ocular involvement. [Time frame: Visit 2 (day 14 ± 7 after screening), 6 months, 12 months and when applicable, at premature withdrawal.]

Eligibility criteria

Inclusion criteria

• Patients over 18 years of age who understand and sign the informed consent form.
• Diagnosis of severe GVHD (graft versus host disease) according to NIH criteria (revised by Lee SJ in 2017) with ocular involvement in the form of severe SOD (severe ocular disease) in both eyes for more than 3 months, objectively defined as superficial punctate keratitis >2 on the Oxford scale (range 0-5) and/or the presence of epithelial defect, and subjectively as severe symptoms, >33 points on the OSDI questionnaire (0-100).
• Patients must have previously been treated for at least three months with blood derivatives and/or insulin eye drops and topical cyclosporine or tacrolimus (unless any of these treatments were not tolerated and had to be discontinued).
• Patients must be using ocular lubricants at least 4 times a day and, despite this, still meet the criteria for severe SOD as outlined in point 2.
• Patients on low doses of topical corticosteroids for maintenance should have a stable dose for at least one month prior to inclusion.
• The dose and frequency of all topical medications the patient begins the trial with must remain unchanged throughout the duration of the trial, unless otherwise judged by the investigator.
• The chronic GVHD systemic treatment should be stable regarding the use of systemic immunosuppressors for at least one month prior to patient inclusion or before starting treatment.
• Negative result in the urine pregnancy test at the baseline visit for women of childbearing age. Subjects must be advised to use contraceptive methods during their participation in the clinical trial and undergo a new pregnancy test at the treatment visit if more than 28 days have passed since the baseline visit.

Exclusion criteria

• Uncontrolled systemic disease or any condition that, in the medical judgment, could put the patient at risk or affect the interpretation of the results.
• Uncontrolled systemic GVHD.
• Active ocular infection.
• Ocular surgery within the last 3 months.
• Initiation of topical therapies for SOD indicated in the inclusion criteria less than 3 months prior to inclusion.
• Start of topical corticosteroid use within 4 weeks prior to inclusion.
• Cognitive impairments that could interfere with study compliance.
• Pregnant women or women during the lactation period.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06905834 · TERAV_24-01_EICRxEYE · 2024-519772-10-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗