Study Procedures

The Diabetic Macular Edema Treated with Ozurdex (DMEO) Study was an investigator-initiated study sponsored by Allergan, Inc (Irvine, California, USA). The protocol was designed by the investigators, who controlled all aspects of the study with no influence from the sponsor. The protocol was approved by the Institutional Review Board of the Johns Hopkins Medical Institutions and was conducted in compliance with the Declaration of Helsinki, US Code 21 of Federal Regulations, and the Harmonized “Tripartite Guidelines for Good Clinical Practice” (1996). The study was registered on February 8, 2013, at www.clinicaltrials.gov ( NCT01790685 ). All patients provided informed consent. Twenty subjects with DME were randomized to Group 1 (dexamethasone implant/anti-VEGF) or Group 2 (anti-VEGF/dexamethasone implant) by the Reading Center and remained masked to group assignment. Randomization sequence was generated using Stata 9.0 (StataCorp, College Station, Texas, USA) statistical software and was stratified by the central subfield thickness (CST >450 μm or <450 μm) with a 1:1 allocation by the Reading Center.

Disease duration was determined from patient reporting and review of records, but only injections documented in records were used to determine the number of prior anti-VEGF injections. Response to prior anti-VEGF therapy was graded as good, moderate, or poor depending on whether all intraretinal fluid could be eliminated by monthly injections or how frequently anti-VEGF injections had to be given to maintain a dry macula. At baseline and at all subsequent visits, subjects had measurement of best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol with examiners masked with regard to treatment group, and ophthalmologic examination including measurement of intraocular pressure, spectral-domain optical coherence tomography (SDOCT) using the Spectralis machine (Heidelberg Engineering, Inc, Carlsbad, California, USA), and an anterior chamber tap. Aqueous samples were stored at −80 C. At baseline, Group 1 patients were given an intraocular injection of a dexamethasone implant in the study eye and Group 2 patients were given an anti-VEGF injection. For dexamethasone implant injections, povidone-iodine was used to clean the conjunctiva and 2% lidocaine was injected under the conjunctiva. The 22 gauge needle of the injector was inserted through the pars plana and the dexamethasone implant was injected into the vitreous cavity. The procedure was similar for anti-VEGF injections except that topical anesthesia and a 30 gauge needle were used. Patients in Group 1 were crossed over to pro re nata (prn) anti-VEGF injections and patients in Group 2 were crossed over to dexamethasone implant at the first visit after week 12 at which there was recurrent/persistent edema.

Anatomic and Functional Outcomes

The major anatomic outcome was excess foveal thickness (EFT), which provides an assessment of the amount of edema; it is calculated by subtracting edema-free CST from measured CST. Normal CST varies among patients, which is particularly true for patients with chronic macular edema who often experience some atrophy from the chronic edema resulting in a relatively thin edema-free CST. Using a single CST threshold such as 320 μm as an indicator of a dry retina could substantially underestimate edema reduction in many patients. Therefore, we used all information at our disposal to obtain the most accurate assessment of edema-free CST and, hence, change in EFT in each patient. For most patients, it was possible to identify 1 or more OCT scans obtained during the study or prior to enrollment on which there was no or minimal edema, but for the few subjects in whom such information was not available, 320 μm was used for normal CST. The functional outcome measure was change from baseline BCVA in ETDRS letter score at each visit. Mixed-effects regression models with a random intercept for eyes to account for the correlation among the repeated measures from the same eye were used to determine if BCVA or CST at each follow-up visit was different from baseline.

Vasoactive Protein Arrays

The levels of vasoactive proteins in aqueous at baseline and each subsequent visit were measured using the Human Angiogenesis Antibody Array Kit (catalog number ARY007; R&D Systems, Inc, Minneapolis, Minnesota, USA). Aqueous samples (115 μL) were blotted on the membrane, which was stored for 16 hours at 4°C and further processed according to the manufacturer’s instructions. Each array membrane was exposed to x-ray film for short-term and long-term exposures. The positive signals detected on the developed x-ray film were quantitated using TotalLab Quant software (Gentel Biosciences, Inc, Madison, Wisconsin, USA).

Correlation of Changes in Vasoactive Proteins With Changes in Edema

The diversity of protein levels and CST were calculated as fold change (log2) in their measurements at each visit relative to appropriate baseline:

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