INCLUSION CRITERIA:
-Participant is 18 years of age or older.
-Diagnosis of diabetic mellitus (type 1 or type 2). Any one of the following will be considered to be sufficient evidence that diabetes is present:
a. Current regular use of insulin for the treatment of diabetes.
b. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes.
c. Documented diabetes by ADA and/or WHO criteria.
-Documented hemoglobin A1C 12% or less within one month of baseline.
-Able and willing to provide informed consent.
-Participant (male or female) agrees to use acceptable birth control methods throughout the course of the study and for three months after completion of treatment. Acceptable methods of birth control include intrauterine device (IUD); oral, dermal ( patch ), implanted or injected contraceptives; tubal ligation; hormonal ring; and barrier methods with spermicide. If a female participant is of child-bearing potential, she must be willing to undergo monthly urine pregnancy tests.
-At least one eye meets the Study Eye Criteria listed under Exclusion Criteria.
EXCLUSION CRITERIA:
-History of chronic renal failure requiring dialysis or kidney transplant.
-Positive serum pregnancy test or currently lactating for women of childbearing potential.
-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). Patients in poor glycemic control who, within the last four months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next four months should not be enrolled.
-Participation in an investigational trial within 30 days of study entry that involved treatment with any drug that has not received regulatory approval at the time of study entry.
-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.
-Laboratory values outside normal limits and considered clinically significant by the investigator.
-Blood pressure greater than 180/110 (systolic above 180 OR diastolic above 110).
-If blood pressure is brought below 180/110 by anti-hypertensive treatment, patient can become eligible.
-History of intravitreal anti-VEGF therapy or subtenon/intravitreal steroids in either eye within three months prior to study entry.
-History of treatment with systemic anti-VEGF agents or steroids within one year prior to study entry.
-Participant is currently taking drugs or ingesting food that affects sirolimus plasma concentrations such as the following:
a. Inhibitors of the CYP3A4 family that could increase sirolimus concentrations (e.g., Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, metoclopramide, nicardipine, troleandomycin, verapamil, ketoconazole, itraconazole, fluconazole, voriconazole, clarithromycin, telithromycin, HIV-protease inhibitors (e.g., ritonavir, indinavir, atazanavir, indinavir, nelfinavir, saquinavir), nefazodone, grapefruit juice)
b. Inducers of the CYP3A4 family that could decrease sirolimus concentrations (e.g., dexamethasone, phenytoin, phenobarbital, carbamazepine, rifampin, rifabutin, rifapentine, St. John's Wort).
STUDY EYE CRITERIA:
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.
STUDY EYE INCLUSION CRITERIA:
-Best-corrected ETDRS visual acuity score of less than or equal to 74 letters (i.e., 20/30 or worse).
-Definite retinal thickening due to diabetic macular edema based on clinical exam involving the center of the macula that is not refractory to further therapy as based on the investigator's clinical judgment.
-Retinal thickness on baseline OCT measurement greater than 250 microns in the central subfield.
-Media clarity, pupillary dilation and patient cooperation sufficient for adequate fundus photographs.
STUDY EYE EXCLUSION CRITERIA:
-Macular edema is considered to be due to a cause other than diabetic macular edema. An eye should not be considered eligible if: (1) the macular edema is considered to be related to cataract extraction or (2) clinical exam and/or OCT suggests that vitreoretinal interface disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of the macular edema.
-An ocular condition is present such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema (e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, nonretinal condition, etc.).
-An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, Irvine-Gass Syndrome, etc.).
-Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).
-History of focal/grid macular photocoagulation within 12 weeks (three months) prior to study entry.
-History of panretinal scatter photocoagulation (PRP) within four months prior to study entry.
-Anticipated need for PRP in the four months following study entry.
-History of prior pars plana vitrectomy.
-History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior six months or anticipated within the next six months following study entry.
-History of YAG capsulotomy performed within two months prior to study entry.
-Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.
-History of treatment within three months prior to enrollment with any drug that has not received regulatory approval at the time of study entry, such as intravitreal or periocular steroids or intravitreal anti-VEGF agents.
-History of treatment with systemic anti-VEGF agents or steroids within one year prior to study entry.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009