Safety and Feasibility of CALEC for LSCD (CALEC)

• ClinicalTrials.gov Identifier: NCT02592330
• Recruitment Status: Recruiting
• First Posted: October 30, 2015
• Last Update Posted: January 31, 2019
• Sponsor: Massachusetts Eye and Ear Infirmary
• Collaborator: Dana-Farber Cancer Institute
• Information provided by (Responsible Party): Massachusetts Eye and Ear Infirmary

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Limbal Stem Cell Deficiency	Biological: CALEC; Procedure: CLAU	Phase 1; Phase 2

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 24 patients with unilateral limbal stem cell deficiency (LSCD). The first 3 participants enrolled will receive the study treatment, CALEC, to assess for safety and feasibility. Subjects 4-24 will be randomized to either the study treatment, CALEC, or to the standard treatment for LSCD, which is conjunctival limbal autograft (CLAU) in a 2:1 ratio.

Participants receiving the study intervention 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 randomized to the standard treatment arm will undergo CLAU surgery, with the biopsy performed at the time of surgery. Investigators, study personnel, and subjects will be aware of the study assignment, given the different procedures required for each, during and after surgery. Subjects will be monitored up to month 24 to assess for any delayed adverse events of the product (CALEC) or procedure as well as assessment of the durability of the transplant.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Feasibility of Cultivated Autologous Limbal Epithelial Cell Transplantation in the Treatment of Limbal Stem Cell Deficiency
• Actual Study Start Date: August 2016
• Estimated Primary Completion Date: February 2020
• Estimated Study Completion Date: February 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: CALEC; The first three subjects enrolled into the study will automatically receive CALEC. Subjects 4-27 will be randomized to either the study treatment, CALEC, or to the standard treatment for LSCD, which is conjunctival limbal autograft (CLAU) in a 2:1 ratio. Participants receiving CALEC 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.	Biological: CALEC; 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.; Other Name: Cultivated Autologous Limbal Epithelial Cell; Procedure: CLAU; Donor tissue is obtained from the fellow eye (limbal autograft) with the goal of transplantation of a new source of epithelium for a diseased ocular surface after the removal of the recipient's scarred and diseased epithelium.; Other Name: Conjunctival Limbal Autograft
Active Comparator: CLAU; Subjects 4-27 will be randomized to either the study treatment, CALEC, or to the standard treatment for LSCD, which is conjunctival limbal autograft (CLAU) in a 2:1 ratio. Subjects randomized to the standard treatment arm will undergo CLAU surgery, with the biopsy performed at the time of surgery.	Procedure: CLAU; Donor tissue is obtained from the fellow eye (limbal autograft) with the goal of transplantation of a new source of epithelium for a diseased ocular surface after the removal of the recipient's scarred and diseased epithelium.; Other Name: Conjunctival Limbal Autograft

Outcome Measures

Primary Outcome Measures :

1. Safety - The following adverse event will serve as a primary safety measure: ocular infection. [ Time Frame: 2 years ]

   To establish that CALEC transplantation has an acceptable safety profile by determining the incidence and severity of ocular adverse events, as identified by eye examination.

   Any adverse events, ocular or systemic, from all subjects will be utilized to summarize safety data for this pilot study. The severity of each adverse event and the relationship of the event to the cell therapy procedure will be assessed. The following adverse event will serve as a primary safety measure: ocular infection.

2. Safety - The following adverse event will serve as a primary safety measure: corneal perforation. [ Time Frame: 2 years ]

   To establish that CALEC transplantation has an acceptable safety profile by determining the incidence and severity of ocular adverse events, as identified by eye examination.

   Any adverse events, ocular or systemic, from all subjects will be utilized to summarize safety data for this pilot study. The severity of each adverse event and the relationship of the event to the cell therapy procedure will be assessed. The following adverse event will serve as a primary safety measure: corneal perforation.

3. Safety - The following adverse event will serve as a primary safety measure: graft detachment ≥ 50%. [ Time Frame: 2 years ]

   To establish that CALEC transplantation has an acceptable safety profile by determining the incidence and severity of ocular adverse events, as identified by eye examination.

   Any adverse events, ocular or systemic, from all subjects will be utilized to summarize safety data for this pilot study. The severity of each adverse event and the relationship of the event to the cell therapy procedure will be assessed. The following adverse event will serve as a primary safety measure: graft detachment ≥ 50%.

4. Feasibility [ Time Frame: 2 years ]

   To establish feasibility of manufacturing CALEC for corneal transplantation.

   Any issues of processing corneal biopsies and development of CALEC constructs will be assessed. The following measure will serve as a primary feasibility measure: cell growth.

5. Feasibility [ Time Frame: 2 years ]

   To establish feasibility of manufacturing CALEC for corneal transplantation.

   Any issues of processing corneal biopsies and development of CALEC constructs will be assessed. The following measure will serve as a primary feasibility measure: cell viability.

6. Feasibility [ Time Frame: 2 years ]

   To establish feasibility of manufacturing CALEC for corneal transplantation.

   Any issues of processing corneal biopsies and development of CALEC constructs will be assessed. The following measure will serve as a primary feasibility measure: culture contamination.

Secondary Outcome Measures :

1. Efficacy [ Time Frame: 2 years ]

   We will assess the efficacy of CALEC transplantation and standard autologous limbal graft on LSCD by comparing pre- and post-operative: corneal surface integrity. This will be defined as:

   • Decrease in frank epithelial defect surface area by >75%, or
   • Decrease in surface staining (NEI grading scale) by >50%
2. Efficacy [ Time Frame: 2 years ]

   We will assess the efficacy of CALEC transplantation and standard autologous limbal graft on LSCD by comparing pre- and post-operative: extent of vascularization. This will be defined as:

   • Decrease in neovascular area by >25%
3. Efficacy [ Time Frame: 2 years ]

   We will assess the efficacy of CALEC transplantation and standard autologous limbal graft on LSCD by comparing pre- and post-operative: patient symptomatology. This information will be determined by assessing:

   • Improvement (decrease) in Ocular Surface Disease Index (OSDI) or Symptom Assessment iN Dry Eye (SANDE)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 79 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female participants age 18 to <80 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

Contacts and Locations

Contacts

Contact: Lynette Johns, OD; 617-596-3655; lynette_johns@meei.harvard.edu

Contact: Stacey Ellender, PhD; 617-573-5507; stacey_ellender@meei.harvard.edu

Locations

United States, Massachusetts

Massachusetts Eye and Ear Infirmary; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Stacey Ellender 617-573-5507 stacey_ellender@meei.harvard.edu

Principal Investigator: Ula Jurkunas, MD

Sub-Investigator: Jia Yin, MD, PhD

Sponsors and Collaborators

Massachusetts Eye and Ear Infirmary

Dana-Farber Cancer Institute

Investigators

• Principal Investigator: Ula Jurkunas, MD; Massachusetts Eye and Ear Infirmary

More Information

• Responsible Party: Massachusetts Eye and Ear Infirmary
• ClinicalTrials.gov Identifier: NCT02592330 History of Changes
• Other Study ID Numbers: 14-124H
• First Posted: October 30, 2015
• Last Update Posted: January 31, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Massachusetts Eye and Ear Infirmary:

CALEC; Limbal Stem Cell Deficiency; LSCD