Eye trauma in falls presenting to the emergency department from 2006 through 2015.

AIMS: To characterise the epidemiology of eye trauma in the event of falls presenting to the emergency departments (ED) in the USA. METHOD: Retrospective cohort study. Nationwide Emergency Department Sample was used to analyse fall encounters presenting to the ED with eye trauma from 2006 to 2015. National estimates of the leading diagnoses were determined, and multivariable regression was used to determine the relationship between factors involved in fall encounters presenting with eye trauma. RESULTS: From 2006 to 2015, an estimated 87 991 036 fall encounters presented to the ED, of which 952 781 encounters had eye trauma as either a primary or secondary diagnosis. The overall incidence of fall encounters with eye trauma per 100 000 US population increased from 30.7 encounters in 2006 to 33.8 encounters per 100 000 population in 2014 with a decrease seen in 2015. Eye trauma, including vision-threatening type, was highest in females (n=500 520, 52.5%), elderly (n=400 209, 42%) and children (n=2 06 741, 21.7%). Elderly were more likely to have eye trauma in the setting of falls (adjusted OR (aOR) 2.06, 95% CI 2.02 to 2.11) and be admitted (aOR 1.89, 95% CI 1.86 to 1.91) than adults (reference). The leading types of eye trauma were contusion of orbital tissues (n=174 292, 18.3%), laceration of eyelid and periocular area (n=172 361, 18.1%) and orbital fractures (n=151 013, 15.8%). CONCLUSIONS: Falls are preventable, yet the incidence of falls and resulting eye trauma are increasing despite our best efforts. As ophthalmologists, we should not only develop guidelines to recognise and counsel at-risk groups under our care but also strategies for prevention of eye trauma secondary to falls.

Classification of disease severity in retinitis pigmentosa.

AIM: To develop a simple and easily applicable classification of disease severity in retinitis pigmentosa (RP). METHODS: This is a retrospective cross-sectional study. Visual acuity (VA), visual field width (VF) and ellipsoid zone width (EZ) were obtained from medical records of patients with RP. A scoring criterion was developed wherein each variable was assigned a score from 0 to 5 depending on its distribution. The cumulative score (from 0 to 15) was used to classify disease severity from grade 0 to 5. The scores were correlated with each other and the final grade. The grades were then correlated with age and disease duration. RESULTS: The median age (range) of patients (n=93) was 55 (12-87) years, 51% were female, 70% had been diagnosed within 10 years, and 50% had autosomal recessive disease. Most eyes (n=181) at least had a VA of 20/40 (67%), a VF of 20° (75%) and an EZ of 5° (76%). All scores were correlated with each other (r=0.509-0.613; p<0.001 for all) and with the final grade (r=0.790-0.869; p<0.001 for all). Except for grade 0 (5%), all grades were evenly distributed: 21% for grade 1, 23% for grade 2, 22% for grade 3, 17% for grade 4 and 12% for grade 5. Grades were correlated with both age (r=0.252; p<0.001) and disease duration (r=0.383; p<0.001). CONCLUSIONS: We present a simple, objective and easy to use disease severity classification for RP which can be used to categorise and compare patients.

Epidemiology of Primary Ophthalmic Inpatient Admissions in the United States.

PURPOSE: To determine the national estimates, demographics, and costs of inpatient eye care in the United States (US). DESIGN: Retrospective cross-sectional study. METHODS: National Inpatient Sample (NIS), a representative sample of all US community hospitals, was used to analyze inpatient admissions with a primary ophthalmic diagnosis from 2001 to 2014. National estimates of the most prevalent diagnoses were determined, and descriptive statistics were calculated for demographics and costs. RESULTS: From 2001 to 2014, there were an estimated 671 324 inpatient admissions (male patients, 51.6%; mean [standard deviation] age, 44.5 [27.3] years) in the US owing to an ophthalmic disorder-an annual rate of 16 per 100 000 population. The Mid-Atlantic region had the highest rate. Most admissions were owing to nontraumatic disorders (75.3%), classified as emergencies (41.8%), and covered by public insurance (48.9%). The median length of stay was 2 days and mortality was 0.2%. The total inflation-adjusted cost over the 14-year period was $5.9 billion. The most prevalent diagnosis was orbital cellulitis (14.5%), followed by orbital floor fracture (9.6%) and eyelid abscess (6.0%). Most diagnoses were infectious (28.0%) and the majority were attributed to external disease (24.3%). A total of 31.1% of all patients had an ophthalmic procedure, pars plana vitrectomy (4.8%) being the most common one. CONCLUSION: There were around 48 000 ophthalmic inpatient admissions in the US costing $421 million every year. Orbital pathology, namely infection and trauma, was the leading cause of admissions. Implementing interventions to decrease the incidence of these conditions may significantly reduce the burden of inpatient ophthalmic care.

Fusion Proteins: Aflibercept (VEGF Trap-Eye).

Vascular endothelial growth factor (VEGF) inhibitors currently used to treat eye diseases have included monoclonal antibodies, antibody fragments, and an aptamer. A different method of achieving VEGF blockade in retinal diseases includes the concept of a cytokine trap. Cytokine traps are being evaluated for the treatment of various diseases that are driven by excessive cytokine levels. Traps, such as VEGF Trap, consist of two extracellular cytokine receptor domains fused together to form a human IgG. Aflibercept (VEGF Trap-Eye) is a soluble fusion protein which combines ligand-binding elements taken from the extracellular components of VEGF receptor (VEGFR)-1 and VEGFR-2 fused to the Fc portion of IgG. This protein contains all human amino-acid sequences, which minimizes the potential for immunogenicity in human patients. The chapter will summarize the chemical properties of aflibercept and the various studies that have demonstrated a role of aflibercept in the management of retinal vascular diseases such as neovascular age-related macular degeneration, diabetic retinopathy, macular edema, and retinal vein occlusion.

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion.

PURPOSE: To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. DESIGN: Secondary outcome measure in randomized double-masked controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. MAIN OUTCOME MEASURES: Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. RESULTS: In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. CONCLUSIONS: Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.

Scatter Photocoagulation Does Not Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion: The RELATE Trial.

PURPOSE: To determine whether scatter and grid laser photocoagulation (laser) adds benefit to ranibizumab injections in patients with macular edema from retinal vein occlusion (RVO) and to compare 0.5-mg with 2.0-mg ranibizumab. DESIGN: Randomized, double-masked, controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 mg or 2.0 mg ranibizumab every 4 weeks for 24 weeks and re-randomized to pro re nata ranibizumab plus laser or ranibizumab alone. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) at week 24 for BCVA at weeks 48, 96, and 144 for second randomization. RESULTS: Mean improvement from baseline BCVA at week 24 was 15.5 and 15.8 letters in the 0.5-mg and 2.0-mg CRVO groups, and 12.1 and 14.6 letters in the 0.5-mg and 2.0-mg BRVO groups. For CRVO, but not BRVO, there was significantly greater reduction from baseline mean central subfield thickness (CST) in the 2.0-mg versus 0.5-mg group (396.1 vs. 253.5 µm; P = 0.03). For the second randomization in CRVO patients, there was no significant difference from week 24 BCVA in the ranibizumab plus laser versus the ranibizumab only groups at week 48 (-3.3 vs. 0.0 letters), week 96 (+0.69 vs. -1.6 letters), or week 144 (+0.4 vs. -6.7 letters), and a significant increase from week 24 mean CST at week 48 (+94.7 vs. +15.2 µm; P = 0.05) but not weeks 96 or 144. For BRVO, there was a significant reduction from week 24 mean BCVA in ranibizumab plus laser versus ranibizumab at week 48 (-7.5 vs. +2.8; P < 0.01) and week 96 (-2.0 vs. +4.8; P < 0.03), but not week 144, and there were no differences in mean CST change from week 24 at weeks 48, 96, or 144. Laser failed to increase edema resolution or to reduce the ranibizumab injections between weeks 24 and 144. CONCLUSIONS: In patients with macular edema resulting from RVO, there was no short-term clinically significant benefit from monthly injections of 2.0-mg versus 0.5-mg ranibizumab injections and no long-term benefit in BCVA, resolution of edema, or number of ranibizumab injections obtained by addition of laser treatment to ranibizumab.

Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.

PURPOSE: To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). METHODS: In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. RESULTS: Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. CONCLUSIONS: Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients.

Importance of proper diagnosis for management: multifocal choroiditis mimicking ocular histoplasmosis syndrome.

PURPOSE: The study aims to evaluate a series of patients with initial diagnosis of ocular histoplasmosis syndrome (OHS) with progression and response to treatments consistent with multifocal choroiditis (MFC). METHODS: Retrospective review of nine patients referred for management of recurrent OHS lesions. Serology panel was conducted to rule out autoimmune and infectious causes. RESULTS: Clinical examination revealed multiple small, punched-out peripheral chorioretinal scars, and peripapillary atrophy. Histoplasma antigen/antibody was negative in all patients. Fluorescein angiography and optical coherence tomography confirmed active inflammation in five patients. Immunomodulatory therapy (IMT) was initiated to control active inflammation. While on IMT, visual acuity stabilized or improved in three patients with no recurrence of CNV or lesion activities over the follow-up period. CONCLUSIONS: MFC may initially masquerade as OHS. Clinical characteristics of recurrent MFC and absence of histoplasma titer may lead to consideration of IMT and other proper treatments for MFC.

Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: One hundred twenty-six patients with DME. METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ. MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24. RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 µm, 286 µm, and 258 µm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 µm or less was 36%, 47%, and 68%, respectively. CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027.

PURPOSE: To assess the safety, tolerability, pharmacokinetics, and dose-limiting toxicity of single intravitreal injection of Sirna-027, a small interfering RNA targeting vascular endothelial growth factor receptor-1, in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (AMD). Secondary objectives included assessment of anatomic changes in retinal thickness, size of CNV, and changes in visual acuity. DESIGN: Prospective, open-label, single-dose, dose-escalation phase 1 study. METHODS: Twenty-six eyes of 26 patients with a median age of 82 years and CNV resulting from AMD who had previous treatments with other therapies were treated at 2 academic retinal practices. Patients received a single dose of Sirna-027 (100, 200, 400, 800, 1200, or 1600 microg/eye). Blood was sampled for pharmacokinetic analysis at 1, 4, and 24 hours after injection and on day 7. Patients underwent ophthalmic examinations including visual acuity, fluorescein angiography, and optical coherence tomography at screening and days 7, 14, 28, and 84. The main outcome measures were adverse reactions and dose-limiting toxicities. RESULTS: Intravitreal injection of a single dose of Sirna-027 from 100 to 1600 microg was well tolerated in patients with AMD, with no dose-limiting toxicity found. Adverse events were mild to moderate in severity. Adjusted mean foveal thickness decreased within 2 weeks after study treatment. The decrease was most pronounced in the 100- and 200-microg doses. CONCLUSIONS: A single intravitreal dose of Sirna-027 up to 1600 microg/eye was well tolerated in patients with CNV resulting from neovascular AMD that had been refractory to other therapies. Stabilization or improvement in visual acuity and foveal thickness was observed. No dose-response or dose-limiting effects were noted.

Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert.

PURPOSE: To compare Iluvien intravitreal inserts that release 0.2 or 0.5 microg/day of fluocinolone acetonide (FA) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: We included 37 patients with DME. METHODS: Subjects with persistent DME despite > or = 1 focal/grid laser therapy were randomized 1:1 to receive an intravitreal insertion of a 0.2- or a 0.5-microg/day insert. MAIN OUTCOME MEASURES: The primary end point was aqueous levels of FA throughout the study with an important secondary outcome of the change from baseline in best-corrected visual acuity (BCVA) at month 12. RESULTS: The mean aqueous level of FA peaked at 3.8 ng/ml at 1 week and 1 month after administration of a 0.5-microg/day insert and was 3.4 and 2.7 ng/ml 1 week and 1 month after administration of a 0.2-microg/day insert. For both inserts, FA levels decreased slowly thereafter and were approximately 1.5 ng/ml for each at month 12. The mean change from baseline in BCVA was 7.5, 6.9, and 5.7 letters at months 3, 6, and 12, respectively, after administration of a 0.5 microg/day-insert and was 5.1, 2.7, and 1.3 letters at months 3, 6, and 12, respectively, after administration of a 0.2-microg/day insert. There was a mild increase in mean intraocular pressure after administration of 0.5-microg/day inserts, but not after administration of 0.2-microg/day inserts. CONCLUSIONS: The FA intravitreal inserts provide excellent sustained intraocular release of FA for > or = 1 year. Although the number of patients in this trial was small, the data suggest that the inserts provide reduction of edema and improvement in BCVA in patients with DME with mild effects on intraocular pressure over the span of 1 year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Topical mecamylamine for diabetic macular edema.

PURPOSE: Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema. DESIGN: A multicenter phase I/II clinical trial. METHODS: Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks. RESULTS: Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine. CONCLUSIONS: This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.

A randomized, double-masked controlled clinical trial of Sandostatin long-acting release depot in patients with postsurgical cystoid macular edema.

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of octreotide, a somatostatin analog, for treatment of postsurgical cystoid macular edema. METHODS: Twenty-one patients with chronic, refractory postsurgical cystoid macular edema and Early Treatment Diabetic Retinopathy Study best-corrected visual acuity of 20/25 to 20/400 were randomized 2:1 to 30 mg monthly intramuscular octreotide or placebo. Outcome measures were visual acuity (primary) and macular thickness and fluorescein angiographic leakage (secondary). RESULTS: Fourteen eyes received octreotide and seven eyes received placebo. Mean duration of cystoid macular edema was 2.65 and 1.99 years for Sandostatin long-acting release and placebo groups, respectively. Visual acuity at 6 months improved > or =2 lines in 7 of 14 eyes (50%) in the treatment group and 0 of 7 eyes in the placebo group (P = 0.046). Improvement in retinal thickening and angiographic leakage occurred in 3 of 13 eyes (23.1%) and 3 of 14 eyes (21.4%) of the treatment group, respectively, and in 1 of 7 eyes (14.3%) (P = 1.0 compared with the treatment group) and 0 of 7 eyes in the placebo group (P = 0.52 compared with the treatment group). The three eyes that improved in all parameters were treated with octreotide. CONCLUSION: Although there were no statistically significant differences between both groups in retinal thickening or angiographic leakage, octreotide-treated patients were more likely to experience a > or =2-line improvement in visual acuity. However, this observation cannot be generalized because of the small sample size.

Retinal thickness analysis by race, gender, and age using Stratus OCT.

PURPOSE: To detect differences in retinal thickness among patients of different race, gender, and age using Stratus OCT. DESIGN: Cross-sectional study. METHODS: In a multicenter, university-based study, 126 patients with no history of ocular disease were enrolled (78 diabetics without retinopathy and 48 nondiabetics). Optical coherence tomography measurements were performed using Stratus OCT. Statistical comparisons of center point foveal thickness and mean foveal thickness were made using generalized estimating equations adjusting for diabetic status, race, age, and gender. RESULTS: The study population consisted of 36% male subjects, 39% Caucasian, 33% African-American, and 28% Hispanic. Mean foveal thickness was 191.6 +/- 2.7 microm and 194.5 +/- 2.7 microm for diabetics and nondiabetics, respectively (P = .49). Mean foveal thickness in male subjects was significantly larger than in female (201.8 +/- 2.7 microm and 186.9 +/- 2.6 microm, respectively; P < .001). Mean foveal thickness was 200.2 +/- 2.7 microm for Caucasian, 181.0 +/- 3.7 microm for African-American, and 194.7 +/- 3.9 microm for Hispanic subjects. Mean foveal thickness was significantly less for African-American than Caucasian (P < .0001) or Hispanic subjects (P = .005). Center point foveal thickness and mean foveal thickness showed a significant increase with age. CONCLUSIONS: There are statistically significant differences in retinal thickness between subjects of different race, gender, and age. When compared to Caucasian and Hispanic subjects, African-American race is a predictor of decreased mean foveal thickness; and male sex (regardless of race) is a significant predictor of increased mean foveal thickness. Mean foveal thickness is similar among diabetics and nondiabetics when data are controlled for age, race, and sex. These results suggest that studies comparing OCT measurements should carefully control for age-based, race-based, and gender-based variations in retinal thickness.

Persistent intermediate uveitis associated with latent manifestation of facial large B-cell non-Hodgkin lymphoma.

PURPOSE: To report a case of intraocular non-Hodgkin lymphoma (NHL) manifesting as persistent intermediate uveitis, facial mass, and Bell palsy. DESIGN: Retrospective, interventional case report. METHODS: A 51-year-old patient with persistent intermediate uveitis for 4 years is diagnosed with intraocular NHL after developing Bell palsy and a facial mass. Initial diagnostic vitrectomy was inconclusive. RESULTS: Subsequent treatment with cyclophosphamide, adriamycin, vincristine, prednisone, and rituximab resulted in regressed facial mass and improved visual acuity. CONCLUSION: NHL can manifest as latent Bell palsy and facial mass in addition to the more common symptoms of uveitis. Intraocular NHL should be suspected in any patient of any age with persistent uveitis.

Monitoring ocular drug therapy by analysis of aqueous samples.

OBJECTIVE: To assess the value of sampling aqueous humor for measurement of potential molecular targets and for pharmacokinetic analysis. DESIGN: Substudy within the context of clinical trials. PARTICIPANTS: Forty patients with macular edema caused by central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), 11 patients with diabetic macular edema (DME), and 8 patients with neovascular age-related macular degeneration (NVAMD). METHODS: Assays for potential molecular targets were performed on aqueous samples from patients participating in drug studies (CRVO, BRVO, and DME) or patients receiving standard care (NVAMD). Ranibizumab levels were measured in patients with CRVO or BRVO after the first and second injections of ranibizumab. MAIN OUTCOME MEASURES: Aqueous levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, and ranibizumab. RESULTS: Aqueous levels of VEGF were significantly higher in patients with DME than in patients with CRVO, which were significantly higher than those in patients with BRVO. Patients with NVAMD had aqueous VEGF levels in an intermediate range, significantly higher than those in patients with BRVO. One month after the second injection of ranibizumab, 27 of 39 patients with vein occlusions had no residual edema; mean aqueous levels of IL-6, IL-1beta, and TNF-alpha were not greater in patients with residual edema; this provides a blueprint for definitive studies with larger cohorts. There was no significant difference in aqueous ranibizumab levels 1 month after the first injection of 0.5 mg versus injection of 0.3 mg, but 1 month after the second injection ranibizumab levels were significantly higher in eyes injected with 0.5 mg. There were substantial differences in levels among patients, but levels in the same patient at months 1 and 2 were highly correlated. No significant difference in aqueous ranibizumab levels was detected between phakic and pseudophakic patients who received the same dose. CONCLUSIONS: These data suggest that aqueous samples are useful for investigating potential involvement of molecular targets in various disease processes and for pharmacokinetic or pharmacodynamic studies.

Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES: To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: A total of 126 patients with DME. METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3, and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients), or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients). MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6. RESULTS: At month 6, the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, P = 0.01, analysis of variance) compared with group 2 (-0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. For patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (P = 0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively. CONCLUSIONS: During a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME.

A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration.

PURPOSE: To determine the safety, tolerability, maximum tolerated dose, and bioactivity of an intravitreal injection of vascular endothelial growth factor (VEGF) Trap-Eye, a fusion protein of binding domains from human VEGF receptors 1 and 2 with human immunoglobulin-G Fc that binds VEGF family members, in patients with neovascular age-related macular degeneration (AMD). DESIGN: Dose-escalation, multicenter, interventional clinical trial. PARTICIPANTS: Twenty-one patients (13 female, 8 male) with neovascular AMD (NVAMD) and lesions or=50% active choroidal neovascularization (CNV) with best-corrected visual acuity (BCVA) or=3 lines and 3 patients requiring no adjunctive treatment of any type for 12 weeks. Some showed elimination of fluorescein leakage and reduction in area of CNV. CONCLUSIONS: Intravitreal injection of up to 4 mg of VEGF Trap-Eye in patients with NVAMD was well tolerated with no evidence of ocular inflammation. Although the number of patients in each cohort was small, there was evidence of bioactivity, because several patients, especially those receiving 2 or 4 mg of VEGF Trap-Eye, showed substantial improvement in BCVA associated with reductions in foveal thickness. Phase III trials to investigate the efficacy of intraocular VEGF Trap-Eye in patients with NVAMD are under way.