This study will test whether sirolimus, a drug approved to treat psoriasis and other
conditions, can help patients with diabetic macular edema. In this disorder, blood vessels
in the retina (a thin layer of tissue that lines the back of the eye) become leaky and the
retina swells. The macula, the center part of the retina that is responsible for fine
vision, may also swell and cause vision loss. Sirolimus inhibits a protein in the body
called mTOR, which plays a critical role in regulating how cells divide and grow. Sirolimus
is also believed to affect the inflammatory process. For both these reasons, the drug may be
helpful in treating diabetic macular edema.
Patients 18 years of age and older with diabetic macular edema may be eligible for this
study. Candidates are screened with the following tests and procedures:
- Medical history, physical examination and blood tests.
- Eye examination assessing visual acuity (eye chart test), eye pressure, pupils, lens
- Eye photography to help evaluate the status of the retina and monitor for changes that
may occur in the future. Special photographs of the inside of the eye are taken using a
camera that flashes a bright light into the eye.
- Fluorescein angiography to evaluate the eye's blood vessels. A yellow dye is injected
into an arm vein and travels to the blood vessels in the eyes. Pictures of the retina
are taken using a camera that flashes a blue light into the eye. The pictures show if
any dye has leaked from the vessels into the retina, indicating possible blood vessel
- Optical coherence tomography to examine retinal thickness. The eye is examined with a
machine that produces cross-sectional pictures of the retina.
Participants undergo the following procedures:
- Sirolimus treatment: One eye is selected as the study eye to receive from two to
seven sirolimus injections (depending on the response to treatment), given every other
month beginning with enrollment. Before the injections are given, numbing eye drops are
applied to the eye and the eye is cleaned with an antiseptic. Patients who require
treatment in the non-study eye receive an FDA-approved treatment such as laser
- Evaluations: Eye examinations, including the tests described above, are repeated every
2 months to evaluate the response to the treatment, check for safety and determine
whether an additional injection should be administered at that visit.
Objective: Diabetic macular edema (DME) is a frequent manifestation of diabetic retinopathy,
a leading cause of blindness in the United States. The only proven treatment for DME is
laser photocoagulation. Sirolimus has been shown to inhibit the production, signaling and
activity of many growth factors relevant to the development of diabetic retinopathy.
Therefore, this study will investigate the safety and efficacy of multiple sirolimus
injections in patients with DME.
Study Population: Eligibility criteria include central macular thickening > 260 microns and
visual acuity 20/32 or worse in one or both eyes.
Design: Five participants will be enrolled into this open-label pilot study. After
receiving two 20 microL (440 micrograms) subconjunctival injections in the study eye at
baseline and Month 2, the participants will be re-evaluated every two months for at least
one year for possible additional injections. During follow-up, participants will not
undergo re-injection if they show significant clinical improvement, defined as no
intraretinal fluid or cysts present on optical coherence tomography (OCT) OR 100% reduction
in excess retinal thickness over 225 microns on OCT OR no leakage on fluorescein angiography
(FA). Beginning at Month 4, participants will be assessed for treatment failure, defined as
loss of 15 or more letters of vision compared to baseline at two consecutive visits OR a 50%
or greater increase in total retinal thickness as measured by OCT at 2 consecutive visits.
Individual participants will be required to suspend treatment and withdraw from study
therapy at any visit in which they are deemed a treatment failure. Participants will have
the option of continuing treatment until a common termination date of one year.
Outcome Measures: The primary outcome is the change in visual acuity in the study eye at six
months compared to baseline. Secondary outcomes include changes in visual acuity in the
study eye at one year as compared with baseline, and changes in retinal thickness as
measured by OCT and changes in fluid leakage in the macula as demonstrated by FA at six
months, one year and throughout the study period in the study and fellow eyes. Safety
outcomes include number and severity of systemic and ocular toxicities, adverse events and
infections, and the number of participants withdrawn from study therapy.
- 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:
1. Current regular use of insulin for the treatment of diabetes.
2. Current regular use of oral anti-hyperglycemia agents for the treatment of
3. 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.
- Both female participants of childbearing potential and male participants able to
father a child must agree to practice two forms of adequate birth control throughout
the course of the study and for three months following the completion of the study
treatment. Acceptable methods of birth control include hormonal contraception (birth
control pills, injected hormones or vaginal ring), intrauterine device, and barrier
methods with spermicide (diaphragm with spermicide, condom and spermicide) or
surgical sterilization (hysterectomy, tubal ligation or vasectomy).
*Participants with a hysterectomy or vasectomy (or who have a partner with a
hysterectomy or vasectomy) are exempt from using two methods of contraception.
However, female participants with tubal ligation (or male participants who have a
female partner with a tubal ligation) are not exempt, and are required to practice
another acceptable method of birth control.
- Female participants of childbearing potential must be willing to undergo pregnancy
testing for the duration of the study.
- At least one eye meets the Study Eye Criteria
- History of chronic renal failure requiring dialysis or kidney transplant.
- Positive serum pregnancy test or currently lactating for women of childbearing
- 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
- 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
- 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
- Laboratory values outside normal limits and considered clinically significant by the
- Blood pressure greater than 180/110 (systolic above 180 OR diastolic above 110).
- 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 one of the following drugs: amprenavir, atazanvir,
clarithromycin, darunavir, delavirdine, erythromycin, bluconazole (at doses of 200 mg
or greater) fluvozamine, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, posaconazole, quinupristin, ritonavir, saquinavir, telithromycin,
troleandomycin, verapamil or voriconazole.
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
- Media clarity, pupillary dilation and patient cooperation sufficient for adequate
STUDY EYE EXCLUSION CRITERIA:
- Macular edema is considered to be due to a cause other than diabetic 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
- 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