Sirolimus for Advanced Age-Related Macular Degeneration

Phase 1

Completed

Conditions: Age-Related Macular Degeneration
Geographic Atrophy

Interventions: Drug: Sirolimus

Registration Number: NCT01445548

Lead Sponsor: National Eye Institute (NEI)

Brief Summary: This study will determine whether a drug called sirolimus is safe to give to people with geographic atrophy (GA) and if it can help preserve vision in patients. GA is an advanced form of dry age-related macular degeneration (AMD). AMD affects the macula, the central part of the retina at the back of the eye needed for sharp, clear vision. There are two types of AMD, wet and dry. In dry AMD, cells in the macula die.

GA may be partially caused by inflammation. Sirolimus helps prevent inflammation and therefore may help people with GA. Researchers want to see whether sirolimus can help prevent vision loss in people with GA.

People at least 56 years of age who have GA related to AMD in both eyes may be eligible for this study.

This study requires at least 8 visits to the National Eye Institute over 1 year. Study visits will be every 2 months for 1 year.

Participants will undergo the following procedures:

* Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, and eye exams. One eye will be selected as the study eye to receive the sirolimus injections.

* Participants will have a sirolimus injection into the study eye at the first visit and every 2 months thereafter unless contraindicated. There will be a follow-up eye exam 1 month after the first injection.

Detailed Description: Objective: Age-related macular degeneration (AMD), the leading cause of blindness in people over age 65 in the United States, is a heterogeneous clinical entity in which retinal degeneration occurs predominantly in the macula in the context of aging and leads to impairment of central visual acuity. AMD occurs in two general forms, one of which involves choroidal neovascularization (CNV) with subsequent formation of a disciform scar. This is often referred to as the neovascular or wet form. A second form, the subject of this study, is termed dry or atrophic macular degeneration and involves a constellation of clinical features that can include drusen, pigment clumping and/or retinal pigment epithelium (RPE) dropout and geographic atrophy (GA). GA can begin as a thinning of the RPE with involvement of the underlying choriocapillaris and subsequently lead to an atrophic change in the macula. Inflammation may play a role in the pathogenesis of GA. Sirolimus inhibits the production, signaling and activity of many inflammatory factors relevant to the development of GA. Therefore, the objective of this study is to investigate the safety and possible efficacy of serial sirolimus intravitreal injections in participants with bilateral GA.

Study Population: Six participants with bilateral GA associated with AMD will be enrolled. Initially, 10 participants with bilateral GA associated with AMD were to be enrolled. However, only six will be enrolled, as sirolimus intravitreal injections will no longer be administered to participants.

Design: In this single-center, prospective, controlled, unmasked, Phase I/II study, one eye of eligible participants was initially randomized to investigational product (intravitreal sirolimus) while the fellow eye was observed. Participants initially received a 20 μL (440 μg) intravitreal injection sirolimus in the study eye at baseline and every two months thereafter unless contraindicated. As of September 2012, sirolimus intravitreal injections were no longer administered to participants. Both the study and fellow eyes will be observed every two months until the study terminates. The study will not terminate until all participants have been followed through Month 12.

Outcome Measures: The primary outcome is the rate of change in area of GA based on masked grading by an external Reading Center of fundus photographs in the study eye and fellow eye at Month 12 compared to baseline. Secondary outcomes will include changes in best-corrected visual acuity (BCVA), changes in drusen area based on masked digital grading of fundus photography, absolute and relative changes in area of GA measured using fundus photography and autofluorescence imaging, and development of exudative AMD measured using optical coherence tomography (OCT). Safety outcomes will include the number and severity of adverse events (AEs). Ocular safety outcomes will be indicated by changes in visual acuity, ocular surface changes, intraocular inflammation and any other ocular changes not consistent with the natural progression of GA.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sirolimus	Sirolimus	Participants initially received a 20 μL (440 μg) intravitreal injection sirolimus in the study eye at baseline and every two months thereafter unless contraindicated. As of September 2012, sirolimus intravitreal injections were no longer administered to participants.

Primary Outcome Measures

Name	Time	Method
Rate of Change in Area of Geographic Atrophy (GA), Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12
Rate of Change in Area of Geographic Atrophy (GA), Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12

Secondary Outcome Measures

Name	Time	Method
Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 12 Months Compared to Baseline	Baseline and Month 12	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. One eye (the study eye) was initially randomized to receive intravitreal sirolimus and the fellow eye was observed as the control.
Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Fellow Eye at 12 Months Compared to Baseline	Baseline and Month 12	Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. One eye (the study eye) was initially randomized to receive intravitreal sirolimus and the fellow eye was observed as the control.
Absolute Change in Total Area of Macular GA, Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for color stereoscopic fundus images by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by subtracting the GA value for the study eye at baseline from the GA value for the study eye at Month 12.
Absolute Change in Total Area of Macular GA, Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for color stereoscopic fundus images by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by subtracting the GA value for the study eye at baseline from the GA value for the study eye at Month 12.
Relative Change in Total Area of Macular GA, Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for color stereoscopic fundus images by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by dividing the absolute change in the total area of GA in the study eye at 12 months by the baseline value.
Relative Change in Total Area of Macular GA, Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for color stereoscopic fundus images by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by dividing the absolute change in the total area of GA in the study eye at 12 months by the baseline value.
Absolute Change in Drusen Area Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	The total area occupied by drusen was determined using planimetry for color stereoscopic fundus images by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). One Macular Photocoagulation Study Disc Area (MPS DA) is equivalent to 1.77 mm\^2 on the retina.
Absolute Change in Drusen Area Based on Masked, Digital Grading of Fundus Photography by an External Reading Center, in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	The total area occupied by drusen was determined using planimetry for color stereoscopic fundus images by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). One Macular Photocoagulation Study Disc Area (MPS DA) is equivalent to 1.77 mm\^2 on the retina.
Absolute Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Modified Fundus Camera (mFC), in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a mFC by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by subtracting the GA value for the study eye at baseline from the GA value for the study eye at Month 12.
Absolute Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Modified Fundus Camera (mFC), in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a mFC by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by subtracting the GA value for the study eye at baseline from the GA value for the study eye at Month 12.
Absolute Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Confocal Scanning Laser Ophthalmoscope (SLO), in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss.The area of GA was determined using planimetry for FAF images obtained with a SLO by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by subtracting the GA value for the study eye at baseline from the GA value for the study eye at Month 12.
Absolute Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Confocal Scanning Laser Ophthalmoscope (SLO), in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a SLO by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by subtracting the GA value for the study eye at baseline from the GA value for the study eye at Month 12.
Relative Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Confocal Scanning Laser Ophthalmoscope (SLO), in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a SLO by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by dividing the absolute change in the total area of GA in the study eye at 12 months by the baseline value.
Relative Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Confocal Scanning Laser Ophthalmoscope (SLO), in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a SLO by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by dividing the absolute change in the total area of GA in the study eye at 12 months by the baseline value.
Relative Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Modified Fundus Camera (mFC), in the Study Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a mFC by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by dividing the absolute change in the total area of GA in the study eye at 12 months by the baseline value.
Relative Change in Area of GA, as Measured by Fundus Autofluorescence (FAF) Imaging Using a Modified Fundus Camera (mFC), in the Fellow Eye at 12 Months Compared to Baseline.	Baseline and Month 12	Geographic atrophy (GA) is the death of photoreceptors and surrounding cells in the retina. The death of these photoreceptors results in lesions that cause vision loss. The area of GA was determined using planimetry for FAF images obtained with a mFC by masked graders at the Doheny Image Reading Center (University of Southern California, Los Angeles, CA). This outcome measure was calculated by dividing the absolute change in the total area of GA in the study eye at 12 months by the baseline value.
Development of Exudative Age-Related Macular Degeneration (AMD) as Measured by Optical Coherence Tomography (OCT) at 12 Months Compared to Baseline	Baseline and 12 Months