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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
30
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.
Change in the integrity of the ocular surface
Significant improvement in the integrity of the ocular surface, measured by corneal staining with fluorescein. A clinically significant improvement is defined as an improvement in Superficial Punctate Keratitis (SPK) of at least one unit compared to baseline, according to the Oxford scale (range 0-5). If an epithelial defect is present, a reduction of at least ¾ of its initial size is required. The Oxford scale is a grading system used to assess ocular surface damage based on corneal and conjunctival staining with fluorescein or lissamine green dyes. It is commonly used to evaluate conditions like dry eye disease and superficial punctate keratitis (SPK). The scale ranges from 0 to 5, where 0 represents no staining (healthy eye) and 5 indicates severe staining and damage.
Time frame: six and twelve months from start of treatment
Change in tear production
Significant increase in tear production, evaluated using the Schirmer test with topical anesthesia, by at least 2 mm. The Schirmer test is a diagnostic test used to measure tear production and assess dry eye syndrome. It evaluates whether the eyes produce enough tears to keep them properly lubricated. Results are as follows: Normal: ≥10 mm of wetting after 5 minutes Mild to moderate dry eye: 5-10 mm Severe dry eye: ≤5 mm
Time frame: six and twelve months from start of treatment
Change in the degree of conjunctival hyperemia
Significant reduction in the degree of conjunctival hyperemia by at least one point (Efron scale, 0-4). The Efron Scale is a clinical grading scale used by eye care professionals to assess the severity of contact lens complications and ocular surface conditions. It provides a standardized way to evaluate changes in the cornea and conjunctiva. The scale ranges from 0 to 4, where: Grade 0 = Normal (No signs of damage) Grade 1 = Trace (Mild changes, barely noticeable) Grade 2 = Mild (Early signs of irritation or damage) Grade 3 = Moderate (Significant changes, requires attention) Grade 4 = Severe (Serious complications, may need treatment)
Time frame: six and twelve months from start of treatment
Change in the parameters related to the Meibomian glands
Significant improvement, by at least one point, in parameters related to the Meibomian glands. The Meibomian glands are specialized sebaceous glands located in the upper and lower eyelids, near the edges of the eyelids. They are crucial for maintaining the health of the ocular surface. When the Meibomian glands become blocked or inflamed, it leads to Meibomian Gland Dysfunction (MGD). This condition can result in Dry eye disease. It is measured using Efron scale. The scale ranges from 0 to 4, where: Grade 0 = Normal (No signs of damage) Grade 1 = Trace (Mild changes, barely noticeable) Grade 2 = Mild (Early signs of irritation or damage) Grade 3 = Moderate (Significant changes, requires attention) Grade 4 = Severe (Serious complications, may need treatment)
Time frame: six and twelve months from start of treatment
Change in any of the findings in the central cornea
Significant improvement in any of the findings in the central cornea, evaluated through in vivo confocal microscopy: 1. Improvement of at least one grade (three grades: corneal, mixed, conjunctival) in the epithelial phenotype. 2. Significant reduction in the density of dendritic cells in the corneal stroma. 3. Improvement in the characteristics of the sub-basal corneal nerve plexus (number of nerves, density, length, tortuosity, and nerve branching). All parameters are evaluated at the same time using the same samples, which will be analyzed by confocal microscopy.
Time frame: six and twelve months from start of treatment
Severity of eye disease measured by WFPRS (Wong-Baker Faces Pain Rating Scale)
The Wong-Baker Faces Pain Rating Scale (WFPRS) is a visual pain assessment tool that uses facial expressions to help individuals describe their pain intensity. The scale consists of six faces, ranging from a happy face (no pain) to a crying face (worst pain possible). Each face corresponds to a numerical value from 0 to 10: 0-No Pain: The patient experiences no discomfort or pain and feels completely normal. 2-Mild Pain: Slight discomfort is present but does not interfere with daily activities. No treatment necessary. 4-Moderate Pain: Noticeable pain or discomfort, which may cause mild difficulty in performing certain tasks but is still manageable. 6-Moderate to Severe Pain: Pain is more persistent and begins to interfere with concentration and daily functions. Medical attention may be needed. 8-Severe Pain: Significant pain that affects daily activities and requires immediate medical attention. 10-Worst Pain Possible: Extreme, unbearable pain that severily limits function.
Time frame: six and twelve months from start of treatment
Severity of eye disease measured by Numerical Rating Scale (NRS)
The Numerical Rating Scale (NRS) is a simple and widely used tool for assessing pain or symptom severity in patients. It typically asks individuals to rate their symptoms on a scale from 0 to 10, where: 0 = No symptoms (or no pain) 10 = Worst possible symptoms (or unbearable pain) In dry eye assessments, the NRS is often used to rate: Eye dryness (0 = no dryness, 10 = extreme dryness) Eye discomfort (0 = no discomfort, 10 = severe discomfort) It helps track symptom progression and evaluate treatment effectiveness over time.
Time frame: six and twelve months from start of treatment
Severity of eye disease measured by Modified Symptom Assessment in Dry Eye Questionnaire (mSIDEQ)
The Modified Symptom Assessment in Dry Eye Questionnaire (mSIDEQ) is a patient-reported questionnaire used to assess the severity and impact of dry eye disease (DED) symptoms. It is an improved version of the original Symptom Assessment in Dry Eye Questionnaire (SIDEQ) and is designed to be more concise and clinically relevant. Patients rate their symptoms on a numerical scale (e.g., 0-4 or 0-5, depending on the version). The total score reflects the overall burden of dry eye symptoms-higher scores indicate worse symptoms.
Time frame: six and twelve months from start of treatment
Severity of eye disease measured by Ocular Surface Disease Index (OSDI)
The Ocular Surface Disease Index (OSDI) is a questionnaire used to assess the severity of dry eye disease (DED) and other ocular surface disorders. It evaluates the frequency of dry eye symptoms, their impact on daily activities, and environmental triggers that might worsen the condition. The OSDI consists of 12 questions divided into three categories: * Ocular Symptoms (e.g., dry eye discomfort, grittiness, pain) * Visual Function (e.g., difficulty reading, driving, using a computer) * Environmental Triggers (e.g., sensitivity to wind or air conditioning) Each question is scored from 0 to 4 (0 = no problems, 4 = severe problems). the results are analised as follows: 0-12 → Normal 13-22 → Mild dry eye 23-32 → Moderate dry eye 33-100 → Severe dry eye
Time frame: six and twelve months from start of treatment
Severity of eye disease measured by CDES-Q (Contact Lens Dry Eye Symptom Questionnaire)
The Contact Lens Dry Eye Symptom Questionnaire (CDES-Q) is a patient-reported questionnaire designed to assess dry eye symptoms in contact lens wearers. It helps evaluate symptom severity, frequency, and impact on daily activities to better understand and manage contact lens-related dry eye (CLDE). Patients typically rate the frequency and severity of symptoms like: * Dryness or discomfort while wearing lenses * Burning or stinging sensations * Foreign body sensation (feeling like something is in the eye) * Blurred vision or fluctuating clarity * Lens awareness or intolerance over time Higher scores indicate more severe dry eye symptoms related to contact lens wear.
Time frame: six and twelve months from start of treatment
Rate of adverse events related to the administration of subconjunctival ASC injection.
The investigator will record in the eCRF and communicate to the sponsor or to the person assuming the tasks delegated by the sponsor, the adverse events (AEs) that are considered of special interest occurring during the study as soon as possible, and no later than 15 days after becoming aware of them. The AEs considered of special interest are: Immunogenicity reactions and their consequences. Adverse events possibly due to unexpected reactions such as hypersensitivity, immunological, toxic reactions, and migration of cells from the application site. Adverse events related to product failure that may be associated with the production process or with the quality of the investigational product.
Time frame: Through study completion, an average of 1 year
Analysis of ocular marker expression in the administered ASCs
The expression of the markers cytokeratin K3 and K12, specific to differentiated corneal epithelium, and the markers K15, nuclear transcription factor p63alpha (p63alpha), and ABCG2 transporter protein, specific to limbal corneal epithelium markers, will be analyzed using an immunodetection technique (immunofluorescence). It will also be analyzed how the freezing process of ASCs may affect these markers and, if possible, establish a correlation between the expression of these markers in the applied cells and the clinical outcomes.
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
The presence and concentration of 48 inflammation-related molecules in tear and serum samples will be studied using the "Human Cytokine/Chemokine/Growth Factor Panel Cat. No. HCYTA-60KPXBK48" kit and XMAP™ technology (Luminex Corporation, Austin, TX, USA). All molecules are analyzed simultaneously, and their concentrations are measured in the same units, allowing for a combined analysis.
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.
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The search for biomarkers aims at the development of predictive models that help improve the diagnosis of EICRc and the prognosis of these patients based on the expression of certain genes.
Time frame: Visit 2 (day 14 ± 7 after screening), 6 months, 12 months and when applicable, at premature withdrawal.