Three-Year Safety and Efficacy of the 0.19-mg Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: The PALADIN Study.

PURPOSE: To assess the long-term safety and efficacy of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (Iluvien; Alimera Sciences, Inc) in patients with diabetic macular edema (DME). DESIGN: Three-year, phase 4, nonrandomized, open-label observational study. PARTICIPANTS: Patients with DME who previously received corticosteroid treatment without a clinically significant rise in intraocular pressure (IOP; all eyes, n = 202 eyes of 159 patients; 36-month completion, n = 94 eyes). METHODS: A prospective, observational study in which patients received a 0.19-mg FAc intravitreal implant at baseline and then were observed for safety-, visual-, anatomic-, and treatment burden-related outcomes for up to 36 months. MAIN OUTCOME MEASURES: Primary safety outcomes included changes in IOP and interventions to manage IOP elevations. Secondary outcomes included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), and adjunctive DME treatment frequency RESULTS: At 36 months after FAc implantation, study eyes showed a mean CST change of -60.69 µm (P < 0.0001) and a mean BCVA change of +3.61 letters (P = 0.0222) compared with baseline. Overall median treatment frequency decreased from 3.4 treatments/year in the 36 months before FAc implantation to 1 treatment/year in the 36 months after FAc implant, a treatment burden reduction of 70.5%. Furthermore, among the group that completed 36 months of treatment (n = 94 eyes), 25.53% of eyes remained rescue free through 36 months. Mean IOP remained stable throughout the study, and IOP increases to more than 30 mmHg occurred in 10.89% of eyes. Intraocular pressure-related procedures were infrequent, with a surgical rate of 2.97%, with 1.49% attributable to steroid use (vs. surgeries attributable primarily to neovascular glaucoma). In addition, an IOP response of < 25 mmHg after the steroid challenge predicted that 96.92% of eyes would have a similar outcome to 0.19-mg FAc implant at the last visit. Intraocular pressure increases that did occur were manageable with standard treatments (n = 202 eyes). CONCLUSIONS: In patients with DME, the 0.19-mg FAc implant provided improved visual outcomes and reduced treatment burden compared with previous treatments while maintaining a favorable safety profile.

Two-year interim safety results of the 0.2 µg/day fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema: the observational PALADIN study.

BACKGROUND: The 0.2 µg/day fluocinolone acetonide (FAc) implant delivers continuous, low-dose, intravitreal corticosteroid for the treatment of diabetic macular oedema (DMO). This ongoing, 3-year, observational clinical trial provides long-term, 'real-world' safety results for the FAc implant in DMO. METHODS: This 24-month interim analysis of a prospective, observational study investigated patients with DMO receiving the commercially available intravitreal 0.2 µg/day FAc implant. The primary outcome was incidence of intraocular pressure (IOP)-lowering procedures. Other IOP-related signals and their relationship to previous corticosteroid exposure, best-corrected visual acuity, central subfield thickness (CST), ocular adverse events and frequency of other treatments were also measured. RESULTS: Data were collected from 95 previously steroid-challenged patients (115 study eyes) for up to 36 months pre-FAc and 24 months post-FAc implant. Mean IOP for the overall population remained stable post-FAc compared with pre-FAc implant. IOP-related procedures remained infrequent (two IOP-lowering surgeries pre-FAc; two trabeculoplasties and four IOP-lowering surgeries post-FAc). Mean visual acuity was stable post-FAc (mean improvement of 1-3 letters) and fewer DMO treatments were required per year following FAc implant. Mean CST was significantly reduced at 24 months post-FAc implant (p<0.001) and the percentage of patients with CST ≤300 µm was significantly increased (p=0.041). CONCLUSION: Few IOP-related procedures were reported during the 24 months post-FAc implant. Positive efficacy outcomes were noted after treatment, with stabilisation of vision and reduction in inflammation, demonstrated by CST. The FAc implant has a favourable benefit-risk profile in the management of DMO, especially when administered after a prior steroid challenge. TRIAL REGISTRATION NUMBER: NCT02424019.

The Evolving Treatment of Diabetic Retinopathy.

PURPOSE: To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy. METHODS: A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance. RESULTS: Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials. CONCLUSION: Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and treatment burden are more constrained. Results with subthreshold laser appear promising but will require more rigorous study to establish its role as adjunctive therapy. Evidence to support an optimal integration of the various treatment options is lacking. Central to the widespread adoption of any therapeutic regimen for DR and DME is substantiation of safety, efficacy, and cost-effectiveness by a body of sound clinical trials.

Effect of oral niacin on central retinal vein occlusion.

PURPOSE: Niacin, a treatment for dyslipidemia, is known to induce vasodilation as a secondary effect. Previous instances of patients with chronic central retinal vein occlusion (CRVO) and cystoid macular edema (CME) have been observed to spontaneously improve when placed on systemic niacin for hypercholesterolemia. The purpose of this study was to evaluate the effects of niacin on CRVO and associated ocular complications. METHODS: A prospective, single-center, non-randomized, interventional case series of niacin for CRVO was conducted. Best-correct visual acuity (BCVA), central macular thickness (CMT), and ocular complications were analyzed in 50 patients over 1 year. Eight patients were controls. RESULTS: The mean initial logMAR BCVA was 0.915, and improved with niacin to 0.745 (P = 0.12), 0.665 (P = 0.02) and 0.658 (P = 0.03) after 3, 6, and 12 months of follow-up, respectively. At baseline, mean CMT was 678.9 µm, and improved to 478.1 µm (P = 0.001), 388.6 µm (P < 0.001), and 317.4 µm (P < 0.001) for the same time points. The control group had a mean initial logMAR BCVA of 1.023, which gradually deteriorated to 1.162 (P = 0.36) after 12 months, and baseline CMT of 700.0 µm at baseline, which gradually improved to 490.9 µm (P = 0.06) after 12 months. Panretinal photocoagulation for neovascularization was required in 5 patients (13.2%) receiving niacin and 3 (37.5%) controls. CONCLUSIONS: These data suggest that niacin may be associated with functional and anatomic improvements in eyes with CRVO. Future investigations will help ascertain whether there is a role for niacin as an adjunct therapy to intravitreal injections in the management of CRVO.

Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection.

OBJECTIVES: To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART). DESIGN AND SETTING: Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California. SUBJECTS: A total of 33 HIV-infected men and women with viral load >10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled. INTERVENTION: Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES: The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo. RESULTS: The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34+/-0.79 vs. 0.81+/-0.18 mmol/L) compared to insignificant change (0.76+/-0.34 vs. 0.76+/-0.22 mmol/L) in the placebo group (ALA vs. placebo: p=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p<0.001 with phytohemagglutinin; p=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2)=0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group. CONCLUSION: Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens.

Quantification of sedimented triamcinolone for intravitreal injection.

PURPOSE: To develop a practical method to concentrate triamcinolone acetonide for intravitreal injection. METHODS: A protocol using sedimentation was developed to increase the concentration of triamcinolone acetonide in a 0.1 mL dose. Two variables were investigated: sedimentation time and initial volume of triamcinolone acetonide. Predetermined volumes (0.2 mL to 1 mL) of triamcinolone acetonide were aspirated into tuberculin syringes. Each syringe was placed in a vertical position for a designated time (0 to 120 minutes). The supernatant was then discarded to reduce the volume to 0.1 mL. High-performance liquid chromatography was then used for quantification of the triamcinolone acetonide. RESULTS: The greatest concentrations of triamcinolone acetonide were seen after 120 minutes of sedimentation. At that time point, the 0.2 mL, 0.3 mL, and 0.5 mL initial volumes resulted in, respectively, 7.4 mg +/- 0.8 mg (mean +/- SE), 9.8 mg +/- 0.2 mg, and 16.4 mg +/- 0.7 mg triamcinolone acetonide in 0.1 mL. The 1.0-mL initial volume resulted in 25.7 mg +/- 0.9 mg triamcinolone acetonide in 0.1 mL; this was the maximum concentration achieved in the experiment. CONCLUSION: The authors have developed a simple protocol to use sedimentation to greatly increase the concentration of triamcinolone acetonide, starting from commercially available triamcinolone acetonide up to a maximum of 25.7 mg per 0.1 mL (257 +/- 9 mg/mL). This study demonstrates a practical and quantifiable method to increase triamcinolone concentration for intravitreal injections.

Prevalence of significant intraocular sequelae in blunt orbital trauma.

The purpose of this study was to describe the prevalence of significant intraocular sequelae (SIOS) and its correlation with the severity of blunt orbital trauma. Four hundred ten consecutive patients presenting to the ED who had sustained blunt orbital trauma were studied. The severity of orbital trauma was graded and SIOS was determined by the presence of an intraocular injury as listed in Table 2. The presence of SIOS was noted in 14 (41.2%) mild, 22 (59.5%) moderate, and 20 (29.4%) severe orbital trauma. In the severe group, the presence of SIOS was detected in 8 (23.5%) blowout fractures and in 12 (35.3%) non-blowout fractures. In view of the high rates of ocular complications among mild and moderate orbital injuries, such patients should have prompt ophthalmic follow up. The relatively low prevalence of SIOS in patients with severe orbital trauma could suggest a protective mechanism in this type of injury.

Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy in HIV infected patients: natural history and clinical predictors.

PURPOSE: To characterize the natural course and clinical predictors of cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients after initiation of highly active antiretroviral therapy (HAART). METHODS: Retrospective analysis of 53 HIV-positive patients (73 eyes with CMV retinitis) treated with and without HAART. All participants continued to take anti-CMV therapy. Survival analysis was used to characterize the natural course of CMV retinitis. Proportional hazards analysis was performed to assess the correlation of the nine potential clinical predictors (baseline CD4 count, post-HAART CD4 count, post-HAART rise in CD4 count, baseline weight, post-HAART rise in weight, post-HAART percentage rise in weight, log of baseline HIV viral load, log of minimum post-HAART HIV viral load, and post-HAART log unit reduction in HIV viral load) with the duration of CMV retinitis remission. RESULTS: Patients receiving HAART had a median CMV retinitis remission duration of 574 days (95% confidence interval, 336-NA) whereas those not receiving HAART had a median remission duration of 80.5 days (95% confidence interval, 28-NA; P < 0.001). Within the HAART-treated population, the minimal viral load reached after HAART was the only clinical predictor to demonstrate significance (P = 0.0075). Several other clinical predictors demonstrated borderline significance; however, this was most likely due to the high correlation of these variables with the minimum post-HAART viral load. A potential secondary clinical predictor identified was the post-HAART rise in CD4 count (P = 0.085). CONCLUSION: With the introduction of HAART, HIV-infected patients have much longer remission durations from recurrent CMV retinitis. The minimum HIV viral load level reached after the initiation of HAART treatment appears to be more important than other clinical variables in the prediction of favorable CMV retinitis remission status. Furthermore, a rise in CD4 T-lymphocyte count by itself appears to be a less significant clinical predictor but may be useful in combination with the HIV viral load data. Selective discontinuation of anti-CMV therapy may be considered in patients with a favorable set of clinical predictors.