Sirolimus for Advanced Age-Related Macular Degeneration

This study is ongoing, but not recruiting participants.
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: August 13, 2013
Last verified: June 2013
  Purpose

Background:

- Age-related macular degeneration (AMD) is a leading cause of blindness in older people. It affects the macula, the part of the retina needed for clear vision. An advanced form of AMD, called geographic atrophy (GA), may be partly caused by inflammation. Sirolimus is a drug that can help prevent inflammation. Researchers want to see if sirolimus can help prevent vision loss in people with GA.

Objectives:

- To determine if sirolimus can help prevent vision loss in people with geographic atrophy.

Eligibility:

  • People at least 56 years of age who have geographic atrophy related to AMD in both eyes.
  • Participants should not have had specific injection- or laser-based AMD therapies, or need eye surgery within the next 2 years.

Design:

  • This study requires at least 15 visits to the National Eye Institute over 2 years. Study visits will be every 2 months for 2 years.
  • 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 study drug.
  • Participants will have a sirolimus injection into the study eye. There will be a followup exam 1 month later, with an eye exam but no injection.
  • Participants will have regular visits with eye exams and injections for 2 years.
  • Two months after the final injection, participants will have a final clinic visit with an eye exam.

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

Study Type: Interventional
Study Design: Allocation: Randomized
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 GA based on masked grading by an external Reading Center of fundus photographs in the study eye and fellow eye at two years compared to baseline. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in best-corrected visual acuity, changes in drusen area, absolute and relative changes in area of GA, and development of exudative AMD. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Enrollment: 6
Study Start Date: September 2011
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Sirolimus
    N/A
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 (micro)L (440 (microg) 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:
  • Participant must be 56 or older.
  • Participant must understand and sign the protocol's informed consent document.
  • Participant must have at least disc area (approximately 1 mm2) 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.
  • Participant must have at least one large druse (greater than or equal to 125 micro m) in each eye.
  • Participants 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.
  • Participant must have a steady fixation in both eyes in the foveal or parafoveal area and media clear enough for good quality photographs. This will permit randomization.
  • Participant must have visual acuity of 20/400 or better in each eye.
  • 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:

  • Participant is actively receiving study therapy in another investigational study.
  • Participant is unable to comply with study procedures or follow-up visits.
  • Participant has 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).
  • Participant 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-VEGF agent for wet/exudative AMD at any point, and 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.
  • Participant has had a vitrectomy.
  • Participant is expected to need ocular surgery during the course of the trial.
  • Participant has undergone lens removal in the last three months or YAG laser capsulotomy within the last month.
  • Participant is on chemotherapy.
  • Participant is on immunosuppressive medication.
  • Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve.
  • Participant has a history of ocular herpes simplex virus (HSV).
  • Participant 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).
  • Participant has a history of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years.
  • Participant has laboratory values outside normal limits and considered clinically significant by the investigator.
  • Participant is currently taking one of the following drugs: amprenavir, atazanvir, 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.
  • Female participant is pregnant or breast-feeding.
  Contacts and Locations
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, M.D. 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
Last Updated: August 13, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Age-Related Macular Degeneration (AMD)
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 April 22, 2014