XTEND: Two-Year Results from a Global Observational Study Investigating Proactive Dosing of Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration.

INTRODUCTION: XTEND (NCT03939767) is a multicenter, observational, prospective study of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in routine clinical practice. The study aims to examine treatment outcomes of proactive intravitreal aflibercept (IVT-AFL) treatment regimens (fixed dosing or treat-and-extend) according to local marketing labels. METHODS: Study eyes received IVT-AFL injections as per the local label. The mean changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to month (M) 12 and M24 were measured and stratified by baseline factors. Treatment exposure and safety data were evaluated. Statistical analysis was descriptive. RESULTS: Overall, 1466 patients from 17 countries were treated. For the overall population, the mean ± standard deviation (SD) age was 78.7 ± 8.5 (range 50-100) years, and 891 patients (60.8%) were female. The mean ± SD baseline BCVA was 54.3 ± 20.3 letters and CST was 374 ± 126 µm. At M12 and M24, mean (95% confidence interval [CI]) BCVA change was + 4.3 (3.4, 5.3) and + 2.3 (1.3, 3.3) letters, respectively. Mean (95% CI) CST was - 106 (- 114, - 99) µm and - 109 (- 117, - 102) µm at M12 and M24, respectively. At M24, 41.5% of patients had a BCVA ≥ 70 letters. Patients received a mean ± SD of 7.7 ± 2.7 injections by M12 and 10.8 ± 5.0 injections by M24 (3.1 injections between M12 and M24). Adverse events were consistent with the known safety profile of IVT-AFL. CONCLUSION: The 24-month results indicate that, in routine clinical practice, a proactive IVT-AFL regimen achieves functional improvements in patients with treatment-naïve nAMD. The proportion of patients achieving ≥ 70 letters at M24 increased, and patients with baseline BCVA ≥ 70 letters maintained vision regardless of the followed IVT-AFL label. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03939767. A video abstract is available for this article. Supplementary file2 (MP4 364624 KB).

Real-World Management of Macular Edema Secondary to Retinal Vein Occlusion with Intravitreal Aflibercept: 24-month Results from the AURIGA Observational Study.

INTRODUCTION: AURIGA is the largest real-world study to date to evaluate intravitreal aflibercept (IVT-AFL) treatment of diabetic macular edema or macular edema secondary to retinal vein occlusion (RVO) in routine clinical practice. Here, we report the 24-month outcomes in the RVO cohort from France, Germany, Italy, and Taiwan. METHODS: AURIGA (NCT03161912) was a prospective observational study. Eligible patients with RVO were enrolled for whom the decision to treat with IVT-AFL had already been made by the attending physician. Patients were treated with IVT-AFL for up to 24 months at physician discretion according to local practice. The primary endpoint was mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters) from baseline to month (M) 12. All statistical analyses were descriptive. RESULTS: In 554 treatment-naïve and 65 previously treated patients with RVO, the respective mean (95% confidence interval) change in VA from baseline was + 12.5 (10.8, 14.3) and + 7.9 (3.3, 12.6) letters by M12 and + 11.4 (9.4, 13.3) and + 4.4 (- 0.6, 9.5) letters by M24 (baseline mean ± standard deviation: 51.0 ± 21.9 and 51.9 ± 20.4 letters); 44.0% of treatment-naïve and 27.9% of previously treated patients reported ≥ 15-letter gains by M24. By M24, the mean change in central retinal thickness from baseline was - 247 (- 267, - 227) µm in treatment-naïve patients and - 147 (- 192, - 102) µm in previously treated patients. From baseline to M6, M12, and M24, treatment-naïve patients received a total of 4.0 ± 1.3, 5.5 ± 2.5, and 6.9 ± 4.2 injections, respectively, and previously treated patients received 3.8 ± 1.5, 5.0 ± 2.2, and 6.3 ± 3.7 injections, respectively. The safety profile of IVT-AFL was consistent with that of previous studies. CONCLUSIONS: In AURIGA, patients with RVO experienced clinically relevant functional and anatomic improvements following IVT-AFL treatment in routine clinical practice. These improvements were largely maintained in treatment-naïve patients over the 24-month study despite the decreasing treatment frequency, suggesting long-term durability of IVT-AFL treatment outcomes. Infographic available for this article. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03161912 (May 19, 2017). INFOGRAPHIC.

Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema in Routine Clinical Practice: Results from the 24-Month AURIGA Observational Study.

INTRODUCTION: AURIGA is the largest real-world study to date to evaluate intravitreal aflibercept (IVT-AFL) in the treatment of diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion in routine clinical practice. The 24-month outcomes in the DME cohort from across 11 participating countries are reported here. METHODS: AURIGA (NCT03161912) was a prospective observational study. The study enrolled eligible patients with DME for whom the decision to treat with IVT-AFL had previously been made by the attending physician. Patients were treated with IVT-AFL for up to 24 months at physician discretion according to local practice. The primary endpoint was mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters) from baseline to month 12 (M12). All statistical analyses were descriptive. RESULTS: In 1478 treatment-naïve and 384 previously treated patients with DME, the mean (95% confidence interval) change in VA from baseline was +6.7 (5.7, 7.6) and +7.4 (5.5, 9.4) letters by M12 and +5.9 (4.9, 6.9) and +8.1 (6.1, 10.1) letters by M24 (baseline [mean ± standard deviation]: 56.0 ± 19.8 and 50.8 ± 19.5 letters), respectively; 25.9% of treatment-naïve and 32.8% of previously treated patients achieved ≥ 15-letter gains by M24. The mean change in central retinal thickness from baseline to M24 was -110 (-119, -102) µm in treatment-naïve patients and -169 (-188, -151) µm in previously treated patients. By M6, M12, and M24, treatment-naïve patients had received 3.8 ± 1.7, 4.9 ± 2.8, and 5.7 ± 3.9 injections, respectively, and previously treated patients had received 3.9 ± 1.5, 4.9 ± 2.4, and 6.2 ± 3.6 injections, respectively. The safety profile of IVT-AFL was consistent with previous studies. CONCLUSION: In AURIGA, treatment-naïve and previously treated patients with DME achieved clinically relevant functional and anatomic improvements following IVT-AFL treatment for up to 24 months in routine clinical practice. Even with the decreasing injection frequency observed, these gains were largely maintained throughout the study, suggesting long-term durability of the positive effects of IVT-AFL treatment. Infographic available for this article. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03161912 (May 19, 2017). INFOGRAPHIC.

Patients with Neovascular Age-Related Macular Degeneration Requiring Intensive Intravitreal Aflibercept Treatment: An ARIES Post Hoc Analysis.

INTRODUCTION: The aim of this post hoc analysis of the ARIES study is to explore the requirement for intravitreal aflibercept (IVT-AFL) treatment intervals of < 8 weeks (w) in patients with neovascular age-related macular degeneration (nAMD), and to assess vision and anatomic outcomes in such patients who require more intensive treatment. METHODS: ARIES was a multicenter, randomized, phase 3b/4 study that investigated the efficacy of two IVT-AFL proactive, individualized, treat-and-extend regimens over 2 years in treatment-naïve patients with nAMD. Patients were determined as injection-intensive if the study investigator identified that a treatment interval of < 8 w was needed and if they had ≥ 1 interval of < 8 w after three initial monthly doses. Treatment intervals could be extended subsequently if extension criteria were met. This is a post hoc analysis of patients enrolled in ARIES and statistical analysis is descriptive. RESULTS: Of 269 patients in the combined treatment arms, 23.0% (n = 62) were injection-intensive (Year 1: 13.8% [n = 37]; Year 2: 9.3% [n = 25]). Time from IVT-AFL initiation to injection-intensive determination varied (range, 16-100 w; median: 43.2 w). Mean treatment interval was 8.4 w before and 6.1 w after injection-intensive determination. Overall, 59.7% achieved treatment intervals of ≥ 8 w following injection-intensive determination. Vision improvements from baseline to Week 104 were smaller for injection-intensive patients than non-injection-intensive patients (mean [SD] best-corrected visual acuity change: + 2.3 [15.6] vs. + 5.9 [12.3] letters). Anatomic outcomes were similar between injection-intensive and non-injection-intensive patients (central retinal thickness change from baseline to Week 104: - 160 [154] vs. - 167 [136] µm). CONCLUSIONS: In ARIES, 23% of treatment-naïve patients with nAMD experienced at least one treatment interval of < 8 w. Injection-intensive patients showed improved vision and anatomic outcomes. For most, treatment intervals could be extended to ≥ 8 w following injection-intensive determination. CLINICALTRIALS: gov Identifier: NCT02581891.

Association Between Visual Acuity and Fluid Compartments with Treat-and-Extend Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: An ARIES Post Hoc Analysis.

INTRODUCTION: Recently, there has been growing interest in exploring the relationship between visual acuity and fluid localization in different retinal compartments. This post hoc analysis of the ARIES study explores the relationship between the presence of intraretinal fluid (IRF) and subretinal fluid (SRF), both at baseline and throughout treatment, and best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) in a treat-and-extend regimen. METHODS: ARIES (NCT02581891) was a multicenter, randomized, phase 3b/4 study comparing the efficacy of two IVT-AFL treat-and-extend regimens over 2 years in patients with treatment-naïve nAMD. This post hoc analysis explores the relationship between the presence of SRF/IRF and absolute BCVA (letter score) at baseline and fixed visits. RESULTS: In 210 patients (treat-and-extend treatment arms combined), SRF presence at baseline was associated at every time point with a numerically higher mean BCVA than if absent, with 10 more letters at week 104. IRF presence at baseline was associated at all but one time point with a numerically lower mean BCVA than if absent (week 104, 8-letter difference). Baseline SRF+IRF was associated with lower BCVA (week 104, 7-letter difference) than if only SRF was present, but higher BCVA (week 104, 8-letter difference) than if only IRF was present. Absence of SRF+IRF was not associated with better BCVA at any time point during the study. CONCLUSION: In ARIES, in patients with nAMD treated with IVT-AFL, the presence of SRF was associated with better visual acuity, whereas IRF was associated with poorer visual acuity. The findings of this post hoc analysis suggest that differentiating IRF from SRF may offer better prognostic value in guiding treatment-extension decisions than the use of combined or "any" IRF and SRF. Prospective trials are needed to validate these results and determine their clinical relevance. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02581891. Association between Visual Acuity and Fluid Compartments with Treat-and-Extend Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: An ARIES Post Hoc Analysis: A Video Abstract (MP4 308264 KB).

EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT USING A TREAT-AND-EXTEND REGIMEN FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: The ARIES Study: A Randomized Clinical Trial.

BACKGROUND/PURPOSE: Treating neovascular age-related macular degeneration with intravitreal aflibercept treat-and-extend (T&E) can reduce treatment burden. ARIES assessed whether intravitreal aflibercept early-start T&E was noninferior to late-start T&E. METHODS: A randomized, open-label, Phase 3b/4 study that included treatment-naïve patients aged ≥50 years with the best-corrected visual acuity 73-25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg intravitreal aflibercept at Week (W) 0, W4, W8, and W16. At W16, patients were randomized 1:1 to early-start (2W interval adjustments) or late-start T&E (8W intervals until W48 then 2W interval adjustments). Primary endpoint: the best-corrected visual acuity change from randomization to W104. RESULTS: Two-hundred seventy-one patients were randomized. The mean (SD) best-corrected visual acuity at baseline was 60.2 (12.1; early-T&E) and 61.3 (10.8; late-T&E) letters. The mean (SD) best-corrected visual acuity change (W16-104) was -2.1 (11.4) versus -0.4 (8.4) letters (early-T&E vs. late-T&E; least-squares mean difference: -2.0; 95% confidence interval: -4.75 to 0.71; P = 0.0162 for noninferior); +4.3 (13.4) versus +7.9 (11.9) letters (W0-104). The mean (SD) number of injections was 12.0 (2.3) versus 13.0 (1.8). From baseline to W104, 93.4% and 96.2% maintained best-corrected visual acuity; the mean (SD) central retinal thickness change was -161.6 (135.6) µm and -158.6 (125.1) µm. The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients. CONCLUSION: Outcomes were similar between patients with neovascular age-related macular degeneration treated with an intravitreal aflibercept early-T&E or late-T&E regimen after initial dosing, with one injection difference over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02581891 https://clinicaltrials.gov/ct2/show/NCT02581891. Supplemental Digital Contents (files 1 http://links.lww.com/IAE/B419).

Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend for Macular Edema in Central Retinal Vein Occlusion: the CENTERA Study.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) treat-and-extend dosing in patients with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: CENTERA (Evaluation of a Treat and Extend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) was an open-label, Phase 4 clinical study. METHODS: Patients received 2 mg of IVT-AFL at baseline and every 4 weeks thereafter, until disease stability criteria were met (or until week 20), at which point treatment intervals were adjusted in 2-week increments based on functional and anatomic outcomes. RESULTS: From baseline to week 76, 105 patients (65.6%) (P <.0001 [test against threshold of 40%]) gained ≥15 letters; and, during the treat-and-extend phase, 72 patients (45.0%) (P = 0.8822 [test against threshold of 50%]) achieved a mean treatment interval of ≥8 weeks. A last and next planned treatment interval of ≥8 weeks was achieved by 101 patients (63.1%) and by 108 patients (67.5%), respectively. Mean ± SD best-corrected visual acuity increased from 51.9 ± 16.8 letters at baseline to 72.3 ± 18.5 letters at week 76 (mean change: +20.3 ± 19.5 letters), and central retinal thickness decreased from 759.9 ± 246.0 µm at baseline to 265.4 ± 57.9 µm at week 76 (mean change: -496.1 ± 252.4 µm). The safety profile of IVT-AFL was consistent with that of previous studies. CONCLUSIONS: Clinically meaningful improvements in functional and anatomic outcomes were achieved with IVT-AFL treat-and-extend dosing. Most patients achieved a last actual and last intended treatment interval of ≥8 weeks; therefore, treatment intervals may have been extended even further with a longer study duration.

Latanoprost 0.005% test formulation is as effective as Xalatan® in patients with ocular hypertension and primary open-angle glaucoma.

PURPOSE: To determine if a test formulation of latanoprost 0.005% (Bausch & Lomb) eyedrops reduced intraocular pressure (IOP) as well as Xalatan® (latanoprost 0.005%) in patients with ocular hypertension (OH) or primary open-angle glaucoma (POAG). METHODS: This multicenter, randomized, investigator-masked, parallel-group study allocated 266 patients with OH or POAG in a 1:1 ratio to latanoprost or Xalatan administered once daily for 6 weeks. The primary endpoint was the mean change in 8:00 AM IOP of the study eye from baseline to week 6. Secondary endpoints included mean change in 8:00 AM IOP from baseline to week 2, and in 12:00 noon and 4:00 PM IOP from baseline to week 2 and week 6. The safety and tolerability of both drugs were also assessed. RESULTS: Both study groups had comparable demographics and baseline characteristics. The mean (SD) change in 8:00 AM IOP from baseline to week 6 was -7.29 (2.61) and -7.54 (2.80) mmHg with latanoprost and Xalatan, respectively. Latanoprost was found noninferior to Xalatan in the primary analysis (mean [SEM] treatment difference, 0.252 [0.504] mmHg; 95% confidence interval [CI] -0.408, 0.913; p = 0.0001; noninferiority margin, 1.5 mmHg) and met the predefined definition of equivalence to Xalatan (95% CI within [-1.5, 1.5 mmHg] margin). The IOP-lowering effects of latanoprost and Xalatan were comparable at all assessed time points. Both study treatments demonstrated a comparable safety and tolerability profile. CONCLUSIONS: Bausch & Lomb latanoprost 0.005% is clinically equivalent to Xalatan for treating OH and POAG as demonstrated through this unique comparative trial.

Inhibition of neutrophil migration and oxygen free radical release by metipranolol and timolol.

Propanolol and metoprolol exert adrenoceptor-independent effects including scavenging of free radicals and inhibition of protein kinase C leading to inhibition of leukocyte migration and radical release as a consequence. Whether topically used metipranolol and timolol exert such effects is unknown. Neutrophil chemotaxis was tested using modified Boyden microchemotaxis chambers. Respiratory burst activity of neutrophils was detected fluorometrically. Radical scavenging properties were tested using 2',7'-dichlorofluorescein diacetate. Metipranolol and timolol inhibited neutrophil chemotaxis at doses in the micromolar range, oxygen free radical production triggered with formyl-Met-Leu-Phe was inhibited at higher concentration. Protein kinase C involvement, suggested to trigger free radical production with phorbol myristate acetate, was antagonized. A direct radical scavenging effect of the beta-blockers was also seen. Inhibition of neutrophil chemotaxis and free radical production is a novel mode of action of metipranolol and timolol that may be relevant for beneficial effects in the topical treatment of eye disease.