Sirolimus for Advanced Age-Related Macular Degeneration (SIRGA2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
ClinicalTrials.gov Identifier:
NCT01445548
First received: September 30, 2011
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

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.

Condition Intervention Phase
Age-Related Macular Degeneration
Geographic Atrophy
Drug: Sirolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study of the Evaluation of Intravitreal Sirolimus in the Treatment of Bilateral Geographic Atrophy Associated With Age-Related Macular Degeneration

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) in the Study Eye at 12 Months Compared to Baseline [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]
    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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 Study Eye at 12 Months Compared to Baseline. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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 Fellow Eye at 12 Months Compared to Baseline. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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. [ Time Frame: Baseline and Month 12 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline and 12 Months ] [ Designated as safety issue: No ]

Enrollment: 6
Study Start Date: September 2011
Study Completion Date: February 2014
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.

Drug: Sirolimus
Other Names:
  • Rapamune®
  • rapamycin

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.

  Eligibility

Ages Eligible for Study:   56 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. 56 or older
  2. Must understand and sign the protocol's informed consent document
  3. Must have at least ½ disc area (approximately 1 mm^2) of GA compatible with AMD present in each eye

    GA is defined as one or more well-defined and often circular patches of partial or complete depigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appears to be preserved and large choroidal vessels are not visible, a round patch of RPE partial depigmentation may be classified as early GA. The GA in each eye must be able to be photographed in their entirety, and it must not be contiguous with any areas of peripapillary atrophy, which can complicate area measurements

  4. Must have at least one large druse (greater than or equal to 125 μm) in each eye
  5. Must not have any evidence or history of exudative disease related to AMD in either eye as determined by a recent fluorescein angiogram performed within 4 months of study enrollment
  6. Must have a steady fixation in both eyes in the foveal or parafoveal area and media clear enough for good quality photographs
  7. Must have visual acuity of 20/400 or better in each eye
  8. Female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse, or agree to practice two acceptable methods of contraception throughout the course of the study and four months after their last study injection. Acceptable methods of contraception include:

    • hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
    • intrauterine device,
    • barrier methods (diaphragm, condom) with spermicide, or
    • surgical sterilization (hysterectomy or tubal ligation).

Exclusion Criteria

  1. Actively receiving study therapy in another investigational study
  2. Unable to comply with study procedures or follow-up visits
  3. Evidence of an ocular disease other than AMD in either eye that may confound the outcome of the study (e.g., diabetic retinopathy with 10 or more hemorrhages or microaneurysms, uveitis, pseudovitelliform macular degeneration moderate/severe myopia)
  4. Has any of the following: a) a history of macular laser, b) a history of photodynamic therapy (PDT), c) received an intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent for wet/exudative AMD at any point, or d) received an intravitreal injection of any other agent (not an anti-VEGF agent) within four months prior to study enrollment

    Participants currently taking or who have previously taken AREDS vitamin supplementation are not excluded.

  5. Has had a vitrectomy
  6. Expected to need ocular surgery during the course of the trial
  7. Has undergone lens removal in the last three months or yttrium aluminum- garnet (YAG) laser capsulotomy within the last month
  8. On chemotherapy
  9. On immunosuppressive medication
  10. On ocular or systemic medications known to be toxic to the lens, retina or optic nerve
  11. History of ocular herpes simplex virus (HSV)
  12. Has a condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control)
  13. Has a history of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years
  14. Has laboratory values outside normal limits and considered clinically significant by the investigator
  15. Is currently taking one of the following drugs: amprenavir, atazanavir, clarithromycin, darunavir, delavirdine, erythromycin, fluconazole (at doses of 200mg or greater), fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, quinupristin, ritonavir, saquinavir, telithromycin, troleandomycin, verapamil or voriconazole
  16. Female participant is pregnant or breast-feeding.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01445548

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Wai T Wong, MD, PhD National Eye Institute (NEI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
ClinicalTrials.gov Identifier: NCT01445548     History of Changes
Other Study ID Numbers: 110249, 11-EI-0249
Study First Received: September 30, 2011
Results First Received: April 7, 2014
Last Updated: May 15, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Age-Related Macular Degeneration (AMD)
Geographic Atrophy
Bilateral Geographic Atrophy
Sirolimus
Age Related Macular Degeneration
AMD

Additional relevant MeSH terms:
Macular Degeneration
Atrophy
Geographic Atrophy
Retinal Degeneration
Retinal Diseases
Eye Diseases
Pathological Conditions, Anatomical
Sirolimus
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 28, 2014