Limbal Stem Cell Deficiency
Conditions
Keywords
LSCD treatment, Limbal Stem Cell Deficiency, CALEC, Cultivated Autologous Limbal Epithelial Cell Transplantation, Corneal epithelial stem cells, Corneal scarring, Corneal opacity, Chemical injury eye, Thermal injury eye, Autologous stem cell, Epithelial defect, Corneal cloudiness, Ocular burn, Ocular injury, Autograft, Conjunctival Limbal Autograft, LSCD research, Chronic contact lens wear, Chronic keratoconjunctivitis, Corneal conjunctivalization, Corneal fibrovascular pannus, Corneal neovascularization, Corneal regeneration, Infectious keratitis, Limbal epithelial stem cell deficiency, Ocular injury drug toxicity, Ocular surface disorder, Neovascularization pannus, Neurotrophic keratitis, Ocular surface Inflammation, Eye injury ionizing radiation, Eye injury ultraviolet radiation, Corneal pannus, Corneal wound healing, Neurotrophic keratopathy, LSCD trial, Stem cell therapy, Epithelial surface integrity, Regrowing corneas
Brief summary
The main aim of the study is to determine the safety and feasibility of a cultivated autologous limbal epithelial cell (CALEC) transplantation in the treatment of limbal stem cell deficiency.
Detailed description
This is an open label, single center study to assess safety, feasibility, and efficacy of Cultivated Autologous Limbal Epithelial Cell (CALEC) grafts in 17 patients with unilateral limbal stem cell deficiency (LSCD). Participants will have a corneal biopsy in their non-diseased eye, which will provide cells for the creation of the CALEC graft. The CALEC will be made at the Good Manufacturing Practice (GMP) Laboratory, Dana Farber Cancer Institute and transported to Mass. Eye and Ear Infirmary for application to the participant's diseased eye during their standard corneal reconstruction procedure. Subjects will be monitored up to month 18 post-transplant to assess for any delayed adverse events of the product (CALEC) or procedure as well as assessment of the durability of the transplant.
Interventions
BIOLOGICALCultivation of Limbal epithelial cells into a graft
A graft is manufactured for transplant
PROCEDURECALEC Transplant
Limbal epithelial cells are obtained from the healthy fellow eye and cultivated in a lab for later transplantation into the diseased eye.
PROCEDUREBiopsy to collect limbal epithelial stem cells that will be cultivated into a graft
Cultivated autologous limbal epithelial cell (CALEC) therapy utilizes a bio-engineered composite of ex vivo expanded autologous corneal epithelial cells and an FDA-approved amniotic membrane (AmnioGraft®, Bio-Tissue, Inc.) to reconstruct the ocular surface. A small biopsy (2-3 mm2) from the patient's contralateral eye serves as a source epithelial (stem) cells that are expanded on the amniotic membrane in culture and the resulting product is surgically transplanted onto the cornea after excision of the fibrovascular pannus.
Sponsors
Dana-Farber Cancer Institute
Massachusetts Eye and Ear Infirmary
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All subjects will receive the study intervention, a stem cell graft cultivated from their own cells.
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Male or female participants age 18 to \<90 years old at time of enrollment * Ability of a subject or guardian/legal representative to provide written informed consent and to comply with study assessments for the full duration of the study. * Patients with unilateral limbal stem cell deficiency (LSCD) as determined by conjunctivalization of the cornea defined by fibrovascular pannus more than 2 mm from the limbus for greater than or equal to 6 clock hours. * Additional optional criteria: * Lack of limbal palisades of Vogt for greater than or equal to 9 clock hours * Goblet cell presence as defined by impression cytologic criteria
Exclusion criteria
* Corneal or ocular surface infection within 30 days prior to study entry or CALEC transplantation * Ocular surface malignancy * Uncontrolled diabetes with most recent HgA1c greater than 8.5% * Renal Failure with eGFR below 60 mL/min per 1.73 m2 * Aspartate aminotransferase and alanine aminotransferase levels greater than 3 times institutional upper limit of normal * Total bilirubin greater than 2 times institutional upper limit of normal (except patients with known Gilbert's syndrome) * Platelet levels less than 100,000 or greater than 450,000 per microliter * Hemoglobin levels of less than 11.0 g/dL in men or less than 10.0 g/dL in women * Prothrombin time greater than 16 seconds and activated partial thromboplastin time greater than 35 seconds in patients not taking warfarin and an international normalized ratio greater than 3 in patients taking warfarin * Inability to tolerate monitored anesthesia * HIV infection or AIDS * Active Hepatitis B or C * Pregnancy (positive test) or lactation * Participation in another simultaneous medical investigation or trial * Severe cicatricial eye disease * Severe dry eye disease as determined by Schirmer's test less than 1mm in at least one eye. * Any medical, psychiatric, debilitating disease/disorder or social condition that in the judgment of the investigator would interfere with or serve as a contraindication to adherence to the study protocol or ability to give informed consent. * Signs of current infection, including fever and current treatment with antibiotics. * History of allo-limbal transplantation * Presence of allergy to the CALEC graft or any of the chemical components within its formulation. Exclusion Based on Donor Eye: * Conjunctivalization of the cornea defined by fibrovascular pannus more than 2 mm from the limbus for greater than or equal to 3 clock hours * Lack of limbal palisades of Vogt for greater than or equal to 3 clock hours * History of allo-limbal transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Safety Events of Interest | 18 Months | The occurrence of the following adverse events at any time during the 18 months of follow-up in the recipient eye will serve as the primary safety events of interest. 1. Ocular Infection (defined as endophthalmitis or microbial keratitis \[bacterial, fungal, parasitic\]: 2. Corneal Perforation 3. Graft Detachment ≥50% |
| Manufacturing Feasibility Measures | 18 Months | Each biopsy attempt will be classified as a feasibility success if it produced at least one construct that met all of the Quality Control (QC) release criteria. Manufacturing feasibility will be evaluate on a biopsy level (denominator is the total number of biopsies).The number and percentage of biopsy attempts resulting in a feasibility success will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measure of Transplant Efficacy | 18 Months | The primary efficacy outcome will be a binary Complete Success of the graft defined as improvement in corneal surface integrity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CALEC Participants undergoing a biopsy with CALEC | 14 |
| CLAU (Control) Participant(s) undergoing a biopsy with CLAU | 1 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Failed Biopsy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | CLAU (Control) | CALEC |
|---|---|---|---|
| Age, Continuous | 46.0 Years | 53.0 Years | 42.0 Years |
| Epithelial Integrity | 15.0 units on a scale | 10.0 units on a scale | 15.0 units on a scale |
| Neovascularization | 7.2 Neovascular Area (% of total area) | 3.6 Neovascular Area (% of total area) | 7.5 Neovascular Area (% of total area) |
| Ocular Surface Disease Index Score | 41.7 units on a scale | 95.5 units on a scale | 40.6 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 13 Participants | 1 Participants | 12 Participants |
| Region of Enrollment United States | 15 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 13 Participants | 0 Participants | 13 Participants |
| Symptom Assessment in Dry Eye Score | 39.1 units on a scale | 72.7 units on a scale | 35.4 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 1 |
| other Total, other adverse events | 16 / 16 | 1 / 1 |
| serious Total, serious adverse events | 1 / 16 | 0 / 1 |
Outcome results
Primary
Manufacturing Feasibility Measures
Each biopsy attempt will be classified as a feasibility success if it produced at least one construct that met all of the Quality Control (QC) release criteria. Manufacturing feasibility will be evaluate on a biopsy level (denominator is the total number of biopsies).The number and percentage of biopsy attempts resulting in a feasibility success will be calculated.
Time frame: 18 Months
Population: Total number of biopsies performed. Fourteen of 16 biopsies (in 15 participants) resulted in a manufacturing success. Two failures occurred in the initial recruitment phase. One of the participant, had a second biopsy and successful transplant; the other elected not to return.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CALEC | Manufacturing Feasibility Measures | 14 Biopsies |
Primary
Primary Safety Events of Interest
The occurrence of the following adverse events at any time during the 18 months of follow-up in the recipient eye will serve as the primary safety events of interest. 1. Ocular Infection (defined as endophthalmitis or microbial keratitis \[bacterial, fungal, parasitic\]: 2. Corneal Perforation 3. Graft Detachment ≥50%
Time frame: 18 Months
Population: All participants receiving a CALEC transplant or CLAU transplant.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CALEC | Primary Safety Events of Interest | Number of Participants with Ocular Infections | 1 Participants |
| CALEC | Primary Safety Events of Interest | Number of Participants with Corneal Perforations | 0 Participants |
| CALEC | Primary Safety Events of Interest | Number of Participants with Graft Detachments | 0 Participants |
| CLAU (Control) | Primary Safety Events of Interest | Number of Participants with Ocular Infections | 0 Participants |
| CLAU (Control) | Primary Safety Events of Interest | Number of Participants with Corneal Perforations | 0 Participants |
| CLAU (Control) | Primary Safety Events of Interest | Number of Participants with Graft Detachments | 0 Participants |
Secondary
Measure of Transplant Efficacy
The primary efficacy outcome will be a binary Complete Success of the graft defined as improvement in corneal surface integrity
Time frame: 18 Months
Population: All participants undergoing a corneal biopsy. The total number of biopsy attempts are summarized.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CALEC | Measure of Transplant Efficacy | Complete Success : 3 Months Post Transplant | 7 Participants |
| CALEC | Measure of Transplant Efficacy | Complete Success : 12 Months Post Transplant | 11 Participants |
| CALEC | Measure of Transplant Efficacy | Complete Success : 18 Months Post Transplant | 10 Participants |
| CLAU (Control) | Measure of Transplant Efficacy | Complete Success : 3 Months Post Transplant | 1 Participants |
| CLAU (Control) | Measure of Transplant Efficacy | Complete Success : 12 Months Post Transplant | 0 Participants |
| CLAU (Control) | Measure of Transplant Efficacy | Complete Success : 18 Months Post Transplant | 1 Participants |