Treatment With Allogeneic Adipose-derived Mesenchymal Stem Cells in Patients With Aqueous Deficient Dry Eye Disease (MESADDE)

The objective of this study is to assess the safety and feasibility of allogeneic adipose tissue-derived mesenchymal stem cells (ASCs) injected into the lacrimal gland in a smaller groups of 7 patients with Aqueous Deficient Dry Eye Disease (ADDE)

Study Overview

• Status: Completed
• Conditions: Dry Eye; Kerato Conjunctivitis Sicca; Aqueous Tear Deficiency
• Intervention / Treatment: Drug: Adipose tissue-derived mesenchymal stem cells

Detailed Description

Dry eye disease (DED) is a very common problem seen in patients all over the world. According to an older study the prevalence of DED in a Danish population 30-60 years of age was 11%. Aqueous tear deficient dry eye (ADDE) is a subtype of DED in which the tear production in the lacrimal gland (LG) is impaired. Current treatment of ADDE is only to relieve symptoms as a curative treatment of ADDE does not exist.

Mesenchymal stem cells (MSCs) reside in almost all connective tissues and are multipotent stem cells with the capacity to differentiate into several kinds of tissue. Several studies have shown that MSCs reduces inflammation in various diseases. Adipose tissue-derived MSCs (ASCs) have gained considerable attention, since they are readily available from the abdominal fat where it is most easily collected and expanded. In resting MSCs, MHC class II is not expressed on the surface, which reduces the inherent immunogenicity of the cells. This supreme attribute allows allogeneic MSC transplantation. Treatment with allogeneic MSCs have been investigated in an extensive number of human subjects for various conditions in clinical trials and no documented adverse events related to an anti-donor immune response exist. One potential advantage of treatment with allogeneic cells is the possibility of their use as an "off-the-shelf" therapeutic agent, avoiding the need for tissue collection and culture to delay and increase the cost of treatment. It has also been suggested that the function of autologous MSCs could be impaired in patients with comorbidities or advanced age.

In canines as in humans the most common cause of ADDE is an immune-mediated inflammatory response targeting the LG. Two studies with injection of allogeneic ASCs from healthy donors in a total of 48 eyes in 27 canines with ADDE have been performed with a significant increase in tear production and no observed adverse events to the treatment.

Studies with injection of ASCs into the human LG has never been conducted. This present study will test the hypothesis that injection of allogeneic ASCs into the LG in patients suffering from ADDE is safe and increases tear production and reduces inflammation resulting in increased ocular comfort.

7 patients with severe ADDE from Dept. of Ophthalmology, Rigshospitalet-Glostrup, will be recruited if they are 1: eligible for the study and 2: sign the informed consent form.

At inclusion the participants will fill out the Ocular Surface Disease Index (OSDI) questionnaire and undergo an eye examination in the following order:

measurement of tear osmolarity (TearLab™), tear break-up time (TBUT), ocular surface staining according to the Ocular SICCA Grading Score, and Schirmer's I test.

After a maximum of 14 days from screening all participants will receive an injection with ASCs into the lacrimal gland on one eye. If both eyes fulfill the eligibility criteria the most affected eye with the lowest tear production assessed with the Schirmer's I test will be the study eye; the contralateral eye will not be treated but examined according to the same protocol as the study eye at each follow-up.

The product used is CSCC_ASC(22) and the dose injected contains approximately 11 million ASCs per LG in a suspension with a total volume of 0.5 ml.

1 week (±2 days), 4 weeks (±4 days), and 4 months (±7 days) after intervention the participants are followed up with eye examination as described above, OSDI questionnaire, and blood test. At 4 months the primary outcomes of safety will be evaluated.

End of trial is defined as last participant's last visit (LPLV) at 3 years late follow-up.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Denmark
  • DK
    • Copenhagen, DK, Denmark, 2200
      • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• OSDI-score > 30
• Schirmer's test 2-5 mm in 5 minutes
• TBUT < 10 sec.

Exclusion Criteria:

• Previously established allergies to Oxybuprocaine or DMSO (rare)
• Reduced immune response (e.g. HIV positive)
• Pregnancy or planned pregnancy within the next 2 years
• Breastfeeding
• Treatment with an anticoagulant that cannot be stopped during the intervention period
• Treatment with systemic medication known to reduce tear production (with an odds ratio >2,0 (3)): anxiolytics, antipsychotics, and inhaled steroids.
• Topical treatment with eye drops other than lubricants
• Any other disease/condition judged by the investigator to be grounds for exclusion, such as infection in or around the eye

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adipose tissue-derived mesenchymal stem cells; Approximately 11 million ASCs in a 0.5 ml suspension	Drug: Adipose tissue-derived mesenchymal stem cells; CSCC_ASC(22), a ready-to-use suspension containing 22 million adipose tissue-derived mesenchymal stem cells per millilitre

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain at injection site: grade	grade 1: mild pain, grade 2: moderate pain, grade 3: severe pain	4 months after treatment
Infection at injection site	grade 1: localized; local intervention indicated, grade 2: oral intervention indicated (antibiotic, antifungal, antiviral), grade 3: intravenously administered (IV) antibiotic, antifungal, or antiviral agent indicated; or operative intervention indicated, grade 4: life-threatening consequences; urgent intervention needed.	4 months after treatment
Bleeding at injection site	Grade 1: Mild bleeding; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization indicated.	4 months after treatment
Eyelid function disorder	Grade 1: Asymptomatic; clinical or diagnostic observations only; intervention not indicated; Grade 2: Symptomatic; nonoperative intervention indicated; limiting instrumental ADL; Grade 3: Limiting self care ADL; operative intervention indicated.	4 months after treatment
Periorbital edema	Grade 1: Soft or non-pitting; Grade 2: Indurated or pitting edema; topical intervention indicated; Grade 3: Edema associated with visual disturbance; increased intraocular pressure, glaucoma or retinal hemorrhage; optic neuritis; diuretics indicated; operative intervention indicated.	4 months after treatment
Ocular discomfort	grade 1: mild discomfort, grade 2: moderate pain, grade 3: disabling pain.	4 months after treatment
Flu-like symptoms	grade 1: Mild flu-like symptoms present; grade 2: Moderate flu-like symptoms, limiting self care ADL; grade 3: Severe flu-like symptoms, limiting self care ADL)	4 months after treatment
Fever	grade 1: 38,0-39,0 Cº; grade 2: >39,0-40,0 Cº; grade 3: >40,0 Cº for ≤ 24 hours; grade 4: >40,0 Cº for > 24 hours	4 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OSDI questionnaire	Change in severity of dry eye symptoms as assessed with the OSDI questionnaire with a score of 0-100, where 0 is "no symptoms" and 100 is "severe symptoms"	4 months after treatment
Schirmer's I test	Change in tear production as evaluated with the Schirmer's I test	4 months after treatment
Tear osmolarity	Change in tear osmolarity measured with TearLab(TM)	4 months after treatment
Ocular SICCA Grading Score	Change in objective signs of DED as evaluated with the Ocular SICCA Grading Score from 0-12 where 0 is "no staining of the ocular surface" and 12 is "severe staining of the ocular surface"	4 months after treatment
HLA anti-bodies	Development of anti-HLA anti-bodies evaluated with Luminex HLA anti-body screening	4 months after treatment

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Study Chair: Steffen Heegaard, MD, DMSc, Department of Ophthalmology, Rigshospitalet-Glostrup, University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2019
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): February 20, 2023

Study Registration Dates

• First Submitted: March 12, 2019
• First Submitted That Met QC Criteria: March 15, 2019
• First Posted (Actual): March 18, 2019

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Lacrimal Apparatus Diseases; Conjunctival Diseases; Keratitis; Corneal Diseases; Eye Diseases; Dry Eye Syndromes; Keratoconjunctivitis Sicca; Conjunctivitis; Keratoconjunctivitis
• Other Study ID Numbers: 001-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No