Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy

This study has been terminated.
(On May 30, 2014, study injections were terminated at the request of the Data and Safety Monitoring Committee. No further recruitment will occur.)
Sponsor:
Collaborators:
The EMMES Corporation
Santen Inc.
Information provided by (Responsible Party):
National Eye Institute (NEI)
ClinicalTrials.gov Identifier:
NCT01675947
First received: August 28, 2012
Last updated: June 20, 2014
Last verified: June 2014
  Purpose

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:

  1. A 20 μL (440 μg) intravitreal (IVT) injection of sirolimus, or
  2. 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:

  1. A clinical evaluation, including safety measures, will occur monthly.
  2. 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.
  3. Fundus autofluorescence will occur at screening/enrollment and at 2, 6, 12, 18 and 24 months after the first injection has occurred.
  4. 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 terminated 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.


Condition Intervention Phase
Geographic Atrophy
Drug: Sirolimus
Drug: Lidocaine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Eye Institute (NEI):

Primary Outcome Measures:
  • Rate of change in area of geographic atrophy [ Time Frame: Every 6 months after enrollment for 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in best-corrected visual acuity [ Time Frame: Every 6 months after enrollment for 2 years ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Number and severity of systemic and ocular toxicities, adverse events and infections [ Time Frame: Monthly for 2 years ] [ Designated as safety issue: Yes ]

Enrollment: 52
Study Start Date: February 2012
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus
Monthly 20 μL (440 μg) intravitreal injection of sirolimus
Drug: Sirolimus
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.
Other Name: Rapamycin, Rapamune
Sham Comparator: Lidocaine
Monthly subconjunctival injection of 2% lidocaine
Drug: Lidocaine
Lidocaine 2%
Other Names:
  • Xylocaine
  • lignocaine

  Eligibility

Ages Eligible for Study:   55 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  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: NCT01675947

Locations
United States, California
Loma Linda University
Loma Linda, California, United States, 92354
University of California, Davis
Sacramento, California, United States, 95817
United States, Florida
University of Florida HSC
Jacksonville, Florida, United States, 32209
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Illinois
Chicago, Illinois, United States, 60612
United States, Maryland
Elman Retina Group
Baltimore, Maryland, United States, 21237
United States, Michigan
Vision Research Foundation
Grand Rapids, Michigan, United States, 49546
United States, North Carolina
Charlotte Eye Ear Nose & Throat Associates
Charlotte, North Carolina, United States, 28210
United States, Pennsylvania
Scheie Eye Institute, University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Palmetto Retina Center
West Columbia, South Carolina, United States, 29169
United States, Tennessee
Southeastern Retina Associates, P.C.
Knoxville, Tennessee, United States, 37909
United States, Texas
Texas Retina Associates
Dallas, Texas, United States, 75231
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
The EMMES Corporation
Santen Inc.
Investigators
Study Chair: Emily Y Chew, MD National Eye Institute (NEI)
  More Information

No publications provided

Responsible Party: National Eye Institute (NEI)
ClinicalTrials.gov Identifier: NCT01675947     History of Changes
Obsolete Identifiers: NCT01664208
Other Study ID Numbers: 3368-12056
Study First Received: August 28, 2012
Last Updated: June 20, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Macular Degeneration
Atrophy
Geographic Atrophy
Retinal Degeneration
Retinal Diseases
Eye Diseases
Pathological Conditions, Anatomical
Lidocaine
Sirolimus
Everolimus
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Cardiovascular Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents

ClinicalTrials.gov processed this record on September 18, 2014