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The alternative pathway of the complement system is implicated in the etiology of age-related macular degeneration (AMD). Complement depletion with pegcetacoplan and avacincaptad pegol are FDA-approved treatments for geographic atrophy in AMD that, while effective, have clinically observed risks of choroidal neovascular (CNV) conversion, optic neuritis, and retinal vasculitis, leaving room for other equally efficacious but safer therapeutics, including Poly Sialic acid (PSA) nanoparticle (PolySia-NP)-actuated complement factor H (CFH) alternative pathway inhibition. Our previous paper demonstrated that PolySia-NP inhibits pro-inflammatory polarization and cytokine release. Here, we extend these findings by investigating the therapeutic potential of PolySia-NP to attenuate the alternative complement pathway. First, we show that PolySia-NP binds CFH and enhances affinity to C3b. Next, we demonstrate that PolySia-NP treatment of human serum suppresses alternative pathway hemolytic activity and C3b deposition. Further, we show that treating human macrophages with PolySia-NP is non-toxic and reduces markers of complement activity. Finally, we describe PolySia-NP-treatment-induced decreases in neovascularization and inflammatory response in a laser-induced CNV mouse model of neovascular AMD. In conclusion, PolySia-NP suppresses alternative pathway complement activity in human serum, human macrophage, and mouse CNV without increasing neovascularization. [ABSTRACT FROM AUTHOR]

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte-derived macrophages (PBMDMs) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring glyco-immune checkpoint control with a sialic acid mimetic agonist targeting microglial/macrophage Siglecs to regain retinal para-inflammatory and inflammatory homeostasis is a promising therapeutic that could halt the progression of and improve visual function in all stages of macular degeneration. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1β, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of nonexudative AMD. [ABSTRACT FROM AUTHOR]

This study aimed to discover the experiences and explored the unheard love (dungngo) language of 'fathers' toward developing parenting programs to increase fathers' involvement in the family. It is a phenomenological research design using the interview as the main research gathering tool. It has a total of 30 father-participants - 10 widows, 10 single fathers, and 10 complete families coming from the different barangays of the municipality of Sta. Cruz, Ilocos Sur. The participant's fathers were chosen through purposive sampling. Based on the data gathered, the following were the findings that described the experiences of different fathers. There are five (5) themes presented, which include Father as Provider, Father as Believer, Fathers' Sorrows, the Fathers' Joy, and Father as Worker. The parenting experience of a Father encountered in rearing their children. There are five (5) themes presented, which include teaching them to be obedient, teaching them to be mature enough, Father as a Guidance Counselor, Father as a sense of hope, and Father as a life changer. The developmental parenting program that could be developed to increase father's involvement are the following 6Bs Developmental Program for fathers: Boost your IQ, Boost Self Confidence, boost your Model Identity, Boost your Bonding Moment, Boost Independence and Boost Parental Rights in the Law. In light of the findings and conclusion of the study, this study can give parenting programs whatever the fathers need in rearing children. Second, parenting programs must be religiously carried out by the municipality for a better understanding of the love language of fathers to increase fathers' involvement in the family. [ABSTRACT FROM AUTHOR]

The article discusses the role of pegaptanib sodium in the treatment of exudative age-related macular degeneration (AMD) and diabetic retinopathy (DR). Topics discussed include the characteristics of pegaptanib and its advantages and disadvantages from anti-vascular endothelial growth factor (VEGF). Also discussed are indications for pegaptanib treatment including exudative AMD, patients with recent ischemic events and DR with large areas of retinal ischemia and glaucoma.

Purpose The Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) trial was designed to evaluate the long-term efficacy and safety profile of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA)/vitreomacular traction, including full-thickness macular hole (FTMH). Design Phase 3b, randomized, sham-controlled, double-masked, multicenter clinical trial. Participants Sample size was 220 subjects (146 ocriplasmin, 74 sham) randomized in a 2:1 ratio to receive intravitreal ocriplasmin 0.125 mg or sham injection. Methods The trial involved 12 visits over 24-months. Inclusion criteria included presence of VMA and best-corrected visual acuity (BCVA) of 20/32 or worse in the study eye. Exclusion criteria included FTMH >400 μm, presence of epiretinal membrane (ERM), and aphakia in the study eye. Main Outcome Measures The primary efficacy end point was the proportion of subjects with pharmacologic VMA resolution at day 28. Secondary efficacy end points were assessed at month 24 and included proportion of subjects with BCVA gain from baseline, nonsurgical FTMH closure, vitrectomy, and Visual Function Questionnaire 25 (VFQ-25) outcomes. Results The OASIS trial met its primary end point with pharmacologic VMA resolution at day 28 being significantly higher in the ocriplasmin group (41.7%) compared with the sham group (6.2%). The treatment effect was maintained until study end. In the ocriplasmin group, pharmacologic VMA resolution at day 28 was higher in subgroups with the following baseline characteristics compared with the complementary subgroups without them: presence of focal VMA, presence of FTMH, absence of ERM, and phakic lens status. In the ocriplasmin group, 50.5% of subjects had a ≥2-line improvement in BCVA from baseline compared with 39.1% of subjects in the sham group. The nonsurgical FTMH closure rate was 30.0% for the ocriplasmin group compared with 15.4% for the sham group. All other secondary end points also favored ocriplasmin over sham. Regarding safety, most adverse events were mild to moderate, had a short onset time, and were transient, with no new safety signals identified. Conclusions The OASIS trial demonstrates the long-term efficacy and safety of ocriplasmin, providing improved resolution of symptomatic VMA compared with previous phase 3 trials with no additional safety signals identified. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of ocular neovascular diseases is being revolutionized by intravitreal therapies targeting vascular endothelial growth factor (VEGF). Two agents are approved for treating neovascular age-related macular degeneration and are being evaluated for other retinal conditions: the RNA aptamer pegaptanib and the monoclonal antibody antigen-binding fragment ranibizumab. Bevacizumab, a related antibody, is being used similarly, although its use is off-label. Pegaptanib selectively binds to a VEGF isoform identified as being especially pathogenic in the eye and spares other isoforms, whereas the other two agents nonselectively bind all VEGF isoforms. Because VEGF is involved in a wide variety of physiologic processes, the ocular and systemic safety of anti-VEGF agents is of paramount concern. I provide an overview of safety data for intravitreal anti-VEGF therapies, focusing primarily on randomized, controlled trials. For pegaptanib, an accumulation of data from pivotal trials and a dedicated systemic safety study have revealed no ocular or systemic safety concerns. For ranibizumab, the principal ocular adverse event detected in clinical trials was a low frequency of ocular inflammation, and systemic adverse events included a slightly elevated risk of nonocular hemorrhage and stroke. Safety data from properly designed randomized controlled trials for bevacizumab are not available. [Copyright &y& Elsevier]

An expert roundtable on clinical decision-making and the nuances of technique. [ABSTRACT FROM AUTHOR]

The article discusses the strategies to maximize cost and procedural efficiencies in regards to intravitreal injections. It examines how the practice has addressed the balancing act of maintaining the safety and efficacy of the procedure while maximizing procedural and patient flow. According to the article, enhancing patient flow can be done by adjusting the process for evaluating and treating intravitreal injection patients, defining the job description of the caregivers and streamlining the documentation process.

Purpose: Vascular endothelial growth factor (VEGF) is a potent ischemia-upregulated angiogenic protein that has been implicated in diabetic retinopathy. Intravitreal VEGF injections have not previously been shown to produce preretinal neovascularization. The purpose of this study was to further characterize the angiopathic changes that occur after intravitreal injections in a nonhuman primate and determine if preretinal neovascularization develops.Design: Experimental animal study.Methods: Vascular endothelial growth factor 165 was injected into the eyes of normal cynomolgus monkeys at regular intervals. As a control, normal eyes were injected with phosphate buffered saline. Color photography and fluorescein angiography were performed at regular intervals. The retinas were incubated for adenosine diphosphatase (ADPase) activity to visualize retinal vessels. The retinas were flat-embedded and areas of potential preretinal neovascularization were identified en bloc and serially sectioned.Results: Areas of capillary nonperfusion and vessel dilation and tortuousity were seen by angiography. In serial sections, the nonperfused areas were found to be associated with endothelial cell hyperplasia in vessel lumens. Preretinal neovascularization originating only from superficial veins and venules was observed throughout peripheral retina, but was not seen in the posterior pole. Lacunae-like veins were subdivided by the process of intussusception and endothelial cell bridging. Arterioles demonstrated endothelial cell hyperplasia and microaneurysms.Conclusion: Intraocular injections of VEGF were sufficient to produce preretinal neovascularization in the nonhuman primate. Most vasculopathic structures were associated with endothelial cell hyperplasia. These results demonstrate that VEGF alone can produce many features of both nonproliferative and proliferative diabetic retinopathy including the previously undescribed development of preretinal neovascularization. This well-characterized VEGF-induced primate model of retinal neovascularization may be useful as a means of testing new treatments for retinal neovascularization. [ABSTRACT FROM AUTHOR]

Discusses the types of retinal detachments and their treatments. Mechanisms of retinal attachment and detachment; Classification of retinal detachments; Risk factors for development of rhegmatogenous retinal detachments.

PURPOSE. In tissues outside the brain, vascular endothelial growth factor-A (VEGF) causes vascular hyper-permeability by opening of inter-endothelial junctions and induction of fenestrations and vesiculo-vacuolar organelles (VVOs). In preliminary studies, we observed that in blood-retinal barrier endothelium, other cellular mechanisms may underlie increased permeability caused by VEGF. This was further investigated in material of an in vivo experimental model of VEGF-induced retinopathy. METHODS. Two monkeys received 4 intravitreal injections of 0.5 μg VEGF in one eye and PBS in the other eye prior to sacrifice at day 9. One monkey received 12 injections of 1.25 μg VEGF in one eye and PBS in the other eye prior to sacrifice at day 24. As a control, an untreated eye of a fourth monkey was studied. RESULTS. In the high-dose VEGF-injected eye, fluorescein angiography showed intense retinal micro-vascular leakage. This leakage was also demonstrated by immunohistochemistry demonstrating extravasation of endogenous fibrinogen and IgG. However, in these leaky blood vessels the number of pinocytotic vesicles (caveolae) at the endothelial luminal membrane were significantly higher and, only in the VEGF-injected eyes, these pinocytotic vesicles transported plasma IgG. By electron microscopy, no fenestrations or VVOs were found in the endothelial cells of the VEGF-injected eyes. CONCLUSION. We conclude that increased vascular permeability for plasma proteins induced by VEGF in blood-retinal barrier endothelium is predominantly caused by a mechanism involving active trans-endothelial transport via pinocytotic vesicles and not by formation of endothelial fenestrations or VVOs. [ABSTRACT FROM AUTHOR]

The article reports that a viable approach to treating retinal vascular disease may be possible based on trials that suggested new drug therapies derived from genetic research. The author notes that a complex, novel method of treating diseases such as age-related macular degeneration may include anti-complement drugs and integrin peptide therapy. According to Doctor Michael Tolentino, developing drug therapies from genetic discoveries is a tricky business, especially in chronic diseases.

Purpose AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME). Design Open-label, dose-escalation clinical trial. Participants Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks. Methods Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks. Main Outcome Measures Safety assessments, change from baseline BCVA, and change from baseline CST. Results All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 μm in 5 patients and by 50 to 100 μm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA. Conclusions No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator. [ABSTRACT FROM AUTHOR]

Purpose The evaluation of the safety and preliminary efficacy of 125 μg ocriplasmin intravitreal injection in patients with focal vitreomacular adhesion (VMA) and exudative age-related macular degeneration (AMD). Design Randomized, sham-injection controlled, double-masked, multicenter, phase II trial. Participants A total of 100 patients with VMA and wet AMD were randomized 3:1 to receive 125 μg ocriplasmin intravitreal injection or sham injection. Methods Study treatment was administered in the mid-vitreous cavity by injection. Post-treatment safety and efficacy assessments were made at baseline and on days 7, 14, and 28 and months 3, 6, and 12 after injection. Secondary efficacy end points were exploratory in nature. Main Outcome Measures The safety and tolerability of ocriplasmin were evaluated. The primary efficacy end point was the proportion of patients with VMA release at day 28 after injection. Secondary end points reported included VMA release over time, total posterior vitreous detachment (PVD), change in visual acuity from baseline, and number of anti–vascular endothelial growth factor (VEGF) injections. Results The safety of ocriplasmin in patients with VMA and wet AMD was shown to be comparable to the known safety profile, with the majority of adverse events in the study eye occurring in the first 7 days after study treatment. A greater proportion of patients achieved VMA resolution and total PVD at month 12 with ocriplasmin compared with sham treatment. There was a decrease in the number of anti-VEGF injections with ocriplasmin at month 12 compared with the sham group, although no differences in visual acuity were observed. Conclusions Ocriplasmin treatment in this population seems to be generally safe and well tolerated and resulted in more patients achieving VMA resolution and PVD with less anti-VEGF use compared with sham treatment. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME). Design: Multicenter, randomized, double-masked, phase 2 clinical trial. Participants: A total of 221 diabetic patients with clinically significant macular edema involving the central macula. Methods: Patients were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed (PRN) basis; or macular laser photocoagulation. Assessments were completed at baseline and every 4 weeks thereafter. Main Outcome Measures: Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks. Results: Patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from +8.5 to +11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only +2.5 letters in the laser group (P ≤ 0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0+, 10+, and 15+ letters were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups versus up to 68%, 32%, and 21% in the laser group, respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from −127.3 to −194.5 μm compared with only −67.9 μm in the laser group (P = 0.0066 for each VEGF Trap-Eye group vs. laser). VEGF Trap-Eye was generally well tolerated. Ocular adverse events in patients treated with VEGF Trap-Eye were generally consistent with those seen with other intravitreal anti-VEGF agents. Conclusions: Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in visual acuity when compared with macular laser photocoagulation in patients with DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Purpose: To investigate in The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study: (1) incidences of neovascular events and retinal capillary nonperfusion (abbreviated as “nonperfusion”), and their relationship with treatment groups; (2) neovascular incidences by nonperfusion status; and (3) pertinent baseline factors for their potential risk for neovascular events. Design: Two multicenter, randomized clinical trials, 1 evaluating participants with central retinal vein occlusion (CRVO) and the other evaluating participants with branch retinal vein occlusion (BRVO). Participants: At 36 months, data were available for 81 participants with CRVO and 128 with BRVO. Intervention: Standard care (observation or grid photocoagulation) versus 1 or 4 mg intravitreal triamcinolone. Main Outcome Measures: Neovascularization of the iris (NVI), neovascular glaucoma (NVG), disc or retinal neovascularization (NVD/NVE), preretinal or vitreous hemorrhage (PRH/VH), and nonperfusion. Results: The cumulative 36-month incidences for CRVO and BRVO eyes, respectively, were 8.5% and 2.4% for NVI or NVG; 8.8% and 7.6% for NVD/NVE or PRH/VH. There were no differences in incidences of neovascular events or risk of nonperfusion when comparing the 3 treatment groups within diseases. For CRVO at 36 months, 16.6% of eyes with ≥5.5 disc areas of nonperfusion versus 4.0% of eyes with <5.5 disc areas of nonperfusion developed NVG (P = 0.0003); for BRVO at 36 months, 14.6% versus 2.4% developed NVD/NVE (P<0.0001). Similar results were noted for most other neovascular events. Nonperfusion was the only significant baseline factor for neovascularization in BRVO, with the risk of a neovascular event increasing with greater disc areas of nonperfusion, and the highest risk noted at ≥5.5 disc areas. Conclusions: In the SCORE Study, triamcinolone treatment was not associated with lower incidences of neovascular events or nonperfusion status compared with observation or grid photocoagulation. Cumulative 36-month incidences for most neovascular events were significantly higher for nonperfused than perfused eyes. Greater baseline disc areas of nonperfusion increased the risk of neovascularization in BRVO but not CRVO eyes, possibly owing to obscuration of retinal capillary details caused by dense hemorrhage at baseline for CRVO eyes. Increased risk of neovascularization was noted below the historical threshold of 10 disc areas of nonperfusion for retinal vein occlusion. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. [Copyright &y& Elsevier]

Neovascularization characterizes diabetic retinopathy and choroidal neovascularization associated with age-related macular degeneration, the most common causes of severe visual loss in the developed world. Gene transfer to the eye using adeno-associated viral (AAV) vectors is a promising new treatment for inherited and acquired ocular diseases. We used an AAV vector with rapid onset and high levels of gene expression in the retina to deliver three anti-angiogenic factors (pigment epithelium-derived factor, tissue inhibitor of metalloproteinase-3, and endostatin) to the eyes of mice in a mouse model of retinopathy of prematurity. All three vectors inhibited ischemia-induced neovascularization. [Copyright &y& Elsevier]

The control, over time and space, of the levels of therapeutic proteins is crucial for successful retinal gene therapy. We tested the ability of adeno-associated viral vectors (AAV) delivered intraocularly to release a secreted protein (erythropoietin (Epo) used as a marker) in the eye, either constitutively or in a pharmacologically regulated manner using the dimerizer-inducible transcriptional regulatory system. Following delivery of a constitutively expressing vector to the intravitreal or subretinal space of nude rats, Epo protein was detected in both the anterior chamber and vitreous fluids. A dual-vector system inducible by the dimerizer rapamycin and expressing Epo was administered into the subretinal space in an attempt to achieve pharmacologic control of trangene expression in the eye. Before induction with rapamycin, the intraocular Epo level was negligible. However, following a systemic administration of rapamycin, Epo was detected in the anterior chamber, peaking on day 3 and returning to baseline 2–3 weeks after withdrawal of the drug. Peak-induced Epo in the anterior chamber was proportional to the dose of rapamycin and was not detected in serum. Similar results were obtained following subretinal administration of the vectors in one nonhuman primate. The rapamycin inducible system promises to be useful for developing gene therapies for inherited retinal degeneration and ocular neovascularization. [Copyright &y& Elsevier]

Objective: To assess the efficacy and safety of intravitreal inserts releasing 0.2 μg/day (low dose) or 0.5 μg/day (high dose) fluocinolone acetonide (FA) in patients with diabetic macular edema (DME). Design: Two parallel, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trials. Participants: Subjects with persistent DME despite at least 1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393). Methods: Subjects received study drug or sham injection at baseline and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year. Main Outcome Measures: The primary outcome was the percentage of patients with improvement from baseline best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Trial (ETDRS) letter score of 15 or more at month 24. Secondary outcomes included other parameters of visual function and foveal thickness (FTH). Results: The percentage of patients with improvement from baseline ETDRS letter score of 15 or more at month 24 was 28.7 and 28.6 in the low- and high-dose insert groups, respectively, compared with 16.2 in the sham group (P = 0.002 for each). Benefit occurred for both doses compared with sham at 3 weeks and all subsequent time points. The mean improvement in BCVA letter score between baseline and month 24 was 4.4 and 5.4 in the low- and high-dose groups, respectively, compared with 1.7 in the sham group (P = 0.02 and P = 0.016). At all time points compared with sham, there was significantly more improvement in FTH. Subjects requiring cataract surgery were more frequent in the insert groups, and their visual benefit was similar to that of subjects who were pseudophakic at baseline. Glaucoma requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the low-dose, high-dose, and sham groups, respectively. Conclusions: Both low- and high-dose FA inserts significantly improved BCVA in patients with DME over 2 years, and the risk-to-benefit ratio was superior for the low-dose insert. This is the first pharmacologic treatment that can be administered by an outpatient injection to provide substantial benefit in patients with DME for at least 2 years. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]