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Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy (Sirolimus)

Primary Purpose

Geographic Atrophy

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Lidocaine
Sponsored by
National Eye Institute (NEI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Geographic Atrophy

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 55 years of age or older. Prior participation in the Age-Related Eye Disease Study 2 (AREDS2) is not required.
  • Participant must understand and sign the protocol's informed consent document.
  • Participant must have central or non-central geographic atrophy (GA) in at least one eye. GA should be at least 0.75 disk areas (DA) in size but no more than 8 disk areas (DA); approximately 2.54 mm2 is 1 DA. GA is defined as one or more well-defined, usually more or less circular patches of partial or complete de-pigmentation of the retinal pigment epithelium (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 de-pigmentation may still be classified as early GA.
  • Participant must have a steady fixation in the study eye in the foveal or parafoveal area and media clear enough for good quality photographs.
  • Participant must have visual acuity between 20/25 and 20/200 in the study eye.
  • Female participants must be post-menopausal.
  • Male participants with female partners capable of conceiving children will be required to use contraception during the study and for four months after their last sirolimus injection.

Exclusion Criteria:

  • Participant is in another investigational study other than AREDS2 and actively receiving study therapy for geographic atrophy or choroidal neovascularization (CNV).
  • Participant is unable to comply with study procedures or follow-up visits.
  • Participant has evidence of ocular disease other than AMD in either eye that may confound the outcome of the study (e.g., glaucoma, diabetic retinopathy with 10 or more hemorrhages or microaneurysms, uveitis, pseudovitelliform macular degeneration, moderate/severe myopia).
  • Participant has received treatment for AMD, such as macular laser, photodynamic therapy (PDT) or anti-vascular endothelial growth factor (anti-VEGF) therapy injection. Or the participant received an IVT injection of any agent (e.g., triamcinolone) other than an anti-VEGF agent within the last four months prior to study enrollment. Vitamin supplementation for AMD is not considered an exclusionary criterion.
  • 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 Yttrium Aluminium Garnet (YAG) laser capsulotomy within the last month.
  • Participant is on chemotherapy.
  • Participant is on immunosuppressive medication or is immunosuppressed.
  • Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve.
  • Participant with a history of malignancy that would compromise the 2-year study survival.
  • Participant with a history of ocular herpes simplex virus (HSV).
  • 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).
  • History of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years that could be worsened by immunosuppression. (The risk of immunosuppression must be determined by an oncology consultation prior to enrollment.)
  • Ocular or periocular inflammation or infection in either eye.
  • Presence of active or inactive toxoplasmosis in the study eye.

Sites / Locations

  • Loma Linda University
  • University of California, Davis
  • University of Florida HSC
  • Emory University
  • University of Illinois
  • Elman Retina Group
  • Vision Research Foundation
  • Charlotte Eye Ear Nose & Throat Associates
  • Scheie Eye Institute, University of Pennsylvania
  • Palmetto Retina Center
  • Southeastern Retina Associates, P.C.
  • Texas Retina Associates
  • University of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Sirolimus

Lidocaine

Arm Description

Monthly 20 μL (440 μg) intravitreal injection of sirolimus

Monthly subconjunctival injection of 2% lidocaine

Outcomes

Primary Outcome Measures

Rate of change in area of geographic atrophy

Secondary Outcome Measures

Change in best-corrected visual acuity

Full Information

First Posted
August 28, 2012
Last Updated
December 8, 2015
Sponsor
National Eye Institute (NEI)
Collaborators
The Emmes Company, LLC, Santen Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01675947
Brief Title
Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy
Acronym
Sirolimus
Official Title
Multi-Center, Randomized, Single Masked Phase 2 Study of Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy Associated With Age-Related Macular Degeneration
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Terminated
Why Stopped
On May 30, 2014, study injections were discontinued at the request of the DSMC. No further recruitment will occur.
Study Start Date
February 2012 (undefined)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
February 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Eye Institute (NEI)
Collaborators
The Emmes Company, LLC, Santen Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will seek to enroll 50 persons who have central or non-central geographic atrophy (GA) associated with age-related macular degeneration (AMD). GA in treated eye must be between 0.75 disk areas (DA) and 8 DA. Eligible participants will be randomly chosen to receive one of the following treatments in the study eye: A 20 μL (440 μg) intravitreal (IVT) injection of sirolimus, or A sham treatment (subconjunctival injection of lidocaine) Participants with two (2) eligible eyes will have one eye randomly assigned to receive intravitreal sirolimus and no sham in the fellow eye. The first injection will begin at Day 0, which may occur on the date of screening/enrollment or up to two weeks following screening/enrollment visit, and every month thereafter. The visit schedule is as follows: A clinical evaluation, including safety measures, will occur monthly. Vision will be measured at the screening/enrollment visit and at 2, 3, 6, 9, 12, 18 and 24 months after the first injection has occurred. Fundus autofluorescence will occur at screening/enrollment and at 2, 6, 12, 18 and 24 months after the first injection has occurred. Fundus color photography and optical coherence tomography will occur at screening/enrollment and at 6, 12, 18 and 24 months after the first injection has occurred. The primary goal is to evaluate whether the persons receiving the sirolimus injections show a slower worsening of geographic atrophy compared to the persons receiving the sham injections. A secondary goal is to evaluate the impact of sirolimus on vision compared to the sham. NOTE: As of May 30, 2014, study injections were discontinued due to safety concerns. No further enrollments will occur and follow-up will continue on all active study participants on a quarterly basis. That is, on visits coinciding with 3 month intervals from date of enrollment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Geographic Atrophy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus
Arm Type
Experimental
Arm Description
Monthly 20 μL (440 μg) intravitreal injection of sirolimus
Arm Title
Lidocaine
Arm Type
Sham Comparator
Arm Description
Monthly subconjunctival injection of 2% lidocaine
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin, Rapamune
Intervention Description
Immunosuppressive agent. Blocks the T-lymphocyte activation and smooth muscle and endothelial cell proliferation that occurs in response to antigenic and cytokine (interleukin IL-2, IL-4 and IL-15) stimulation through either Ca2+-dependent or Ca2+-independent pathways. Sirolimus arrests cell cycle progression by direct interaction with two intracellular proteins (immunophilin FK binding protein 12 (FKBP-12) and the mammalian target of rapamycin (mTOR), a multifunctional serine-threonine kinase). In cells, sirolimus binds to FKBP-12, and the resulting sirolimus-FKBP-12 complex then binds to and inhibits mTOR.
Intervention Type
Drug
Intervention Name(s)
Lidocaine
Other Intervention Name(s)
Xylocaine, lignocaine
Intervention Description
Lidocaine 2%
Primary Outcome Measure Information:
Title
Rate of change in area of geographic atrophy
Time Frame
Every 6 months after enrollment for 2 years
Secondary Outcome Measure Information:
Title
Change in best-corrected visual acuity
Time Frame
Every 6 months after enrollment for 2 years
Other Pre-specified Outcome Measures:
Title
Number and severity of systemic and ocular toxicities, adverse events and infections
Time Frame
Monthly for 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 55 years of age or older. Prior participation in the Age-Related Eye Disease Study 2 (AREDS2) is not required. Participant must understand and sign the protocol's informed consent document. Participant must have central or non-central geographic atrophy (GA) in at least one eye. GA should be at least 0.75 disk areas (DA) in size but no more than 8 disk areas (DA); approximately 2.54 mm2 is 1 DA. GA is defined as one or more well-defined, usually more or less circular patches of partial or complete de-pigmentation of the retinal pigment epithelium (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 de-pigmentation may still be classified as early GA. Participant must have a steady fixation in the study eye in the foveal or parafoveal area and media clear enough for good quality photographs. Participant must have visual acuity between 20/25 and 20/200 in the study eye. Female participants must be post-menopausal. Male participants with female partners capable of conceiving children will be required to use contraception during the study and for four months after their last sirolimus injection. Exclusion Criteria: Participant is in another investigational study other than AREDS2 and actively receiving study therapy for geographic atrophy or choroidal neovascularization (CNV). Participant is unable to comply with study procedures or follow-up visits. Participant has evidence of ocular disease other than AMD in either eye that may confound the outcome of the study (e.g., glaucoma, diabetic retinopathy with 10 or more hemorrhages or microaneurysms, uveitis, pseudovitelliform macular degeneration, moderate/severe myopia). Participant has received treatment for AMD, such as macular laser, photodynamic therapy (PDT) or anti-vascular endothelial growth factor (anti-VEGF) therapy injection. Or the participant received an IVT injection of any agent (e.g., triamcinolone) other than an anti-VEGF agent within the last four months prior to study enrollment. Vitamin supplementation for AMD is not considered an exclusionary criterion. 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 Yttrium Aluminium Garnet (YAG) laser capsulotomy within the last month. Participant is on chemotherapy. Participant is on immunosuppressive medication or is immunosuppressed. Participant is on ocular or systemic medications known to be toxic to the lens, retina or optic nerve. Participant with a history of malignancy that would compromise the 2-year study survival. Participant with a history of ocular herpes simplex virus (HSV). 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). History of cancer (other than a non-melanoma skin cancer) diagnosed within the past five years that could be worsened by immunosuppression. (The risk of immunosuppression must be determined by an oncology consultation prior to enrollment.) Ocular or periocular inflammation or infection in either eye. Presence of active or inactive toxoplasmosis in the study eye.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emily Y Chew, MD
Organizational Affiliation
National Eye Institute (NEI)
Official's Role
Study Chair
Facility Information:
Facility Name
Loma Linda University
City
Loma Linda
State/Province
California
ZIP/Postal Code
92354
Country
United States
Facility Name
University of California, Davis
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
University of Florida HSC
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Illinois
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Elman Retina Group
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21237
Country
United States
Facility Name
Vision Research Foundation
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49546
Country
United States
Facility Name
Charlotte Eye Ear Nose & Throat Associates
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28210
Country
United States
Facility Name
Scheie Eye Institute, University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Palmetto Retina Center
City
West Columbia
State/Province
South Carolina
ZIP/Postal Code
29169
Country
United States
Facility Name
Southeastern Retina Associates, P.C.
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37909
Country
United States
Facility Name
Texas Retina Associates
City
Dallas
State/Province
Texas
ZIP/Postal Code
75231
Country
United States
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53705
Country
United States

12. IPD Sharing Statement

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Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy

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