Sirolimus to Treat Diabetic Macular Edema

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 a 20 μL (440 μg) subconjunctival injection 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 or treatment success, defined as no intraretinal fluid or cysts present on optical coherence tomography (OCT) OR 100% reduction in excess retinal thickness over 260 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 two consecutive visits. Individual participants deemed treatment failures will continue receiving sirolimus injections, but will be allowed to receive focal laser therapy for any amenable leaking microaneurysms at Month 4. Beginning at Month 6, focal laser therapy will be permitted for both treatment failures and participants who do not meet the criteria of a treatment success. 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, 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.


Eligibility Criteria:
Participant-Level Inclusion Criteria

1. Participant is 18 years of age or older.
2. 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 diabetes.
   3. Documented diabetes by American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria.
3. Documented hemoglobin A1C 12% or less within one month of baseline.
4. Able and willing to provide informed consent.
5. 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, 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 a 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.
6. Female participants of childbearing potential must be willing to undergo pregnancy testing for the duration of the study.
7. At least one eye meets the study eye criteria listed in Section 4.2.

Participant-Level Exclusion Criteria

1. History of chronic renal failure requiring dialysis or kidney transplant.
2. Positive serum or urine pregnancy test or currently lactating for women of childbearing potential.
3. 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).
4. 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.
5. 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.
6. Laboratory values outside normal limits and considered clinically significant by the investigator.
7. Blood pressure \> 180/110 (systolic above 180 OR diastolic above 110).
8. History of intravitreal anti-VEGF therapy or subtenon/intravitreal steroids in either eye within three months prior to study entry.
9. History of treatment with systemic anti-VEGF agents or steroids within one year prior to study entry.
10. Participant is currently taking one of the following drugs: amprenavir, atazanavir, 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.

Study Eye Inclusion Criteria

1. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity score of ≤ 74 letters (i.e., 20/32 or worse).
2. 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.
3. Retinal thickness on baseline OCT measurement \> 260 microns in the central subfield.
4. Media clarity, pupillary dilation and patient cooperation sufficient for adequate fundus photographs.

Study Eye Exclusion Criteria

1. Macular edema is considered to be due to a cause other than diabetic macular edema.
2. 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.).
3. 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.).
4. 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).
5. History of focal/grid macular photocoagulation within 12 weeks (three months) prior to study entry.
6. History of panretinal scatter photocoagulation (PRP) within four months prior to study entry.
7. Anticipated need for PRP in the four months following study entry.
8. History of prior pars plana vitrectomy.
9. 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.
10. History of (Yttrium Aluminium Garnet) YAG laser capsulotomy performed within two months prior to study entry.
11. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.