This is a clinical study where patients with diabetes and a vision threatening eye condition called "Diabetic Macular Edema" receive four injections into the eye at monthly intervals. The patients will already have tried the standard of care without complete success. The patients will be randomized to receive either a high dose, a low dose or a sham control treatment. The study will evaluate whether the new treatment improves vision and whether it changes the underlying course of the disease in the eye.

Inclusion Criteria:

• Confirmed diagnosis of Type I or Type II diabetes mellitus (DM).
• BCVA of ≥19 letters (~20/400) and ≤73 letters (~20/40) in the study eye and ≥34 letters(~20/200 or better) in the fellow eye.
• Presence of ciDME in the study eye defined as CST ≥305 μm in women and ≥320 μm in men
• Subjects first anti-VEGF injection in the study eye occurred ≤36 months.
• Subjects have received at least 3 anti-vascular endothelial growth factor (VEGF) injections in the study eye within a 6-month period.
• The last anti-VEGF injection in the study eye is ≥ 8 weeks.

Exclusion Criteria:

• Evidence of ocular pathology (e.g. visually significant cataract) that impacts subject's vision in the study eye from any cause other than DME.
• Evidence/presence of amblyopia, vitreomacular traction, epiretinal membrane, foveal atrophy, or foveal ischemia, or any other condition in the macula that is thought to impair the subject's vision (other than DME).
• Prior treatment with panretinal photocoagulation or focal grid macular photocoagulation in the study eye within the previous 3 months.
• Prior treatment with intravitreal (IVT) steroid in the study eye (in the previous 3 months for triamcinolone, previous 6 months for Ozurdex and at any time for Iluvien).
• Prior treatment with topical NSAIDs or topical steroids in the study eye within 1 month.
• Prior treatment with systemic corticosteroids or systemic anti-VEGF therapy within 3 months.
• Prior vitrectomy in the study eye.
• Prior intraocular surgery in the study eye except for cataract surgery. Cataract surgery within the previous 6 months in the study eye is excluded.
• Intraocular pressure (IOP) of >22 mmHg in the study eye or use of >2 antiglaucoma agents (combination agents count as 2 agents) in the study eye.
• Evidence of infectious dacrocystitis, significant blepharitis, active conjunctivitis, infectious keratitis, or scleritis in either eye, or any other condition that might affect the safety of the IVT injection.
• Current active proliferative diabetic retinopathy (PDR), active anterior segment neovascularization (ASNV), active retinal neovascularization, or the presence of vitreous hemorrhage in the study eye.
• Poorly controlled DM.
• Uncontrolled hypertension
• Prior treatment with ocriplasminin the study eye within 3 months