A Phase I/IIa Trial for Autologous Transplantation of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for Geographic Atrophy Associated With Age-Related Macular Degeneration

National Eye Institute (NEI)2 sites in 1 country20 target enrollmentSeptember 23, 2020

ConditionsDry Age-Related Macular Degeneration Geographic Atrophy

InterventionsiPSC-derived RPE/PLGA transplantation

DrugsiPSC-derived RPE/PLGA transplantation

Overview

Phase: Phase 1
Intervention: iPSC-derived RPE/PLGA transplantation
Conditions: Dry Age-Related Macular Degeneration
Sponsor: National Eye Institute (NEI)
Enrollment: 20
Locations: 2
Primary Endpoint: Summary of adverse events
Status: Recruiting
Last Updated: 2 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

Background:

Age-related macular degeneration is a common eye disease in people over 50. The "dry" form of the disease can worsen into geographic atrophy, causing blind spots. Researchers want to learn if replacing older eye cells with younger ones can help treat this disease.

Objective:

To test the safety of putting cells inside the eye as a possible future treatment for dry age-related macular degeneration.

Eligibility:

People ages 55 and older who have geographic atrophy with loss of vision. People who have had "wet" macular degeneration in study eye are NOT eligible.

Design:

Participants will be screened with:

Medical history
Physical exam
Blood and urine tests
Eye exam
Eye photos
Fluorescein angiography. An intravenous (IV) line is placed in an arm vein. A dye is injected. A camera takes pictures of the dye as it flows through the eyes' blood vessels.
Electroretinography. An electrode is taped to participants' forehead. They sit in the dark. After 30 minutes, numbing eye drops and contact lenses are placed in their eyes. They watch flashing lights.
Tuberculosis test
Chest X-ray
Electrocardiography. Sticky pads are placed on participants' chest to record the heart's electrical activity.

Participants will have at least 14 study visits over 5 and a half years. They will repeat screening tests.

Participants will have retinal pigment epithelium (RPE) transplantation surgery in one eye. For this, cells from participants' blood are turned into RPE cells. These cells are placed in their eye through a cut in their retina. They will get dilating eye drops, an IV line, and anesthesia that may make them sleep. A gas bubble will be put in their eye to help it heal. Participants will receive immunosuppressive medications to avoid transplant rejection.

Participants will be contacted yearly for up to 15 years.

Detailed Description

Age-related macular degeneration (AMD) is a leading cause of vision loss among the elderly. There are limited treatment options for geographic atrophy (GA), the advanced stage of dry AMD, in which cells of the neurosensory retina and associated retinal pigment epithelium (RPE) gradually degenerate and die. Advances in stem cell biology allowing differentiation of pluripotent cells into RPE in vitro make feasible a cell-based strategy for potential treatment of AMD, and recent methods for induced pluripotent stem cell (iPSC) generation offer promise of individualized autologous therapy. Such an approach involves generation of iPSC from somatic cells taken from a patient with GA, differentiation of iPSC into RPE grown as a monolayer on a thin scaffold in vitro, and transplantation of the RPE/scaffold construct into a small region in the subretinal space of the same patient, with a goal of rescuing the overlying neurosensory retina from further degeneration. Objective: To evaluate the safety and feasibility of subretinal transplantation of iPSC-derived RPE, grown as a monolayer on a biodegradable poly lactic-co-glycolic acid (PLGA) scaffold, as a potential autologous cell-based therapy for GA associated with AMD. Study Population: Five participants will undergo RPE transplantation in one eye. Eligible eyes will have GA, best-corrected visual acuity (BCVA) between 20/100 and inclusive of counting fingers (CF), and a fellow eye that has same or better BCVA. If the National Eye Institute (NEI) Data and Safety Monitoring Committee (DSMC) gives clearance to proceed based on review of data from the first cohort, a second cohort of up to seven additional participants with GA, BCVA between 20/80 and CF (inclusive) in the eye being considered for RPE transplantation, and same or better visual acuity in the other eye may undergo the procedure to gather additional safety and potential efficacy data useful for planning future studies. Up to 20 participants may be enrolled to allow for screening failures, for participants withdrawing from the study prior to RPE transplantation, or cases where the RPE cell transplantation does not occur due to intraoperative surgical considerations. Design: In this phase I/IIa, prospective, single-arm, multi-center clinical trial, participants will undergo subretinal transplantation of autologous iPSC-derived RPE in one eye and will be followed for five years after surgery. Outcome Measures: The primary outcome measure is the safety of RPE/PLGA transplantation, as determined by assessment of visual acuity change and summary of adverse events at 12 months after RPE/PLGA transplantation. Secondary outcome measures include visual acuity change and adverse event reporting at 24 and 60 months, and changes in the following at 12, 24 and 60 months as compared with baseline, assessed in the transplanted region, and compared where applicable with other areas in the macula, and/or with corresponding regions in the fellow eye: retinal sensitivity and fixation parameters assessed by microperimetry; multifocal electroretinography (mfERG) responses; macular structure on cross-sectional and en face imaging by optical coherence tomography (OCT); macular features on color, single-wavelength reflectance, and fundus autofluorescence (FAF) photography; and fluorescein angiography (FA). Some NEI and JHU participants may undergo imaging of photoreceptor/RPE features using adaptive-optics-assisted macular imaging under a separate NEI protocol (e.g., 15-EI-0020).

Registry

clinicaltrials.gov

Start Date

September 23, 2020

End Date

May 31, 2029

Last Updated

2 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

National Eye Institute (NEI)

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•INCLUSION CRITERIA:
•Participant Eligibility Criteria:
•To be eligible, the following inclusion criteria must be met, where applicable.
•Participant must be 55 years of age or older.
•Participant must have a diagnosis of dry AMD, defined as presence (or history, as documented in available color fundus photographs) of at least one medium or large druse (greater than or equal to 63 micrometer diameter) in the macula in at least one eye; AND presence of GA in at least one eye.
•Participant must understand and sign the protocol s informed consent document.
•Any participant of childbearing potential must have a negative pregnancy test at screening and must be willing to undergo pregnancy testing prior to RPE transplantation.
•Any participant of childbearing potential and any participant able to father children who has a partner of childbearing potential must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse, or must agree to practice an effective method of contraception through Month 12 in the study. Acceptable methods of contraception include:
•Hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
•Intrauterine device,

Exclusion Criteria

•listed below. The fellow eye must also meet the relevant eligibility criteria listed below.
•Study Eye Inclusion Criteria:
•The study eye must have one or more regions of geographic atrophy with total area of 1 disc area or more. A region of geographic atrophy is defined as an area of uniform hypofluorescence on fundus autofluorescence (FAF) imaging, with greatest linear dimension at least 500 micrometer, with a border within 500 micrometer of the foveal center, not compatible with pigmentary changes, drusen, RPE detachment, drusenoid RPE detachment, hemorrhage, or other lesion. (Note: If macular geographic atrophy is contiguous with peripapillary atrophy, complicating calculation of total area, only atrophy temporal to a vertical line placed a half disc diameter temporal to the temporal border of the disc will be included in the total area of geographic atrophy calculated for eligibility purposes.)
•For participants in the first cohort, the study eye must have an ETDRS best-corrected visual acuity (BCVA) letter score of \<= 53 and \>= CF (i.e., Snellen equivalent between 20/100 and CF), and the fellow eye must have a letter score no more than five letters worse than the study eye using Electronic Visual Acuity (EVA) testing. If the study eye is CF vision, then the fellow eye must be both (1) CF or better vision and (2) subjectively as good or better than the study eye according to the subject s perception. (Note: Letter scores within five or fewer letters of each other are accordingly considered equal for eligibility determination, and other factors may be used to select the study eye if both are eligible by BCVA.
•For participants in the second cohort, the study eye must have an ETDRS best-corrected visual acuity (BCVA) letter score of \<= 58 and \>= CF (i.e., Snellen equivalent between 20/80 and CF), and the fellow eye must have a letter score no more than five letters worse than the study eye using Electronic Visual Acuity (EVA) testing. If the study eye is CF vision, then the fellow eye must be both (1) CF or better vision and (2) subjectively as good or better than the study eye according to the subject s perception. (Note: Letter scores within five or fewer letters of each other are accordingly considered equal for eligibility determination, and other factors may be used to select the study eye if both are eligible by BCVA.
•The compromise in visual acuity for the study eye must be judged predominantly secondary to dry AMD, in the judgment of the investigator.
•The study eye must have clarity of ocular media and degree of pupil dilation sufficient to permit adequate fundus photography and safe vitrectomy surgery.
•The study eye must be either pseudophakic or aphakic.
•EXCLUSION CRITERIA:
•A participant is not eligible if any of the following exclusion criteria are present: