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Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR : A Randomized Controlled Trial.
Ohji, M, Takahashi, K, Okada, AA, Kobayashi, M, Matsuda, Y, Terano, Y, ,
Advances in therapy. 2020;(3):1173-1187
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Abstract
PURPOSE To evaluate efficacy and safety of intravitreal injections of aflibercept (IVT-AFL) treat-and-extend (T&E) dosing regimens in treatment-naïve patients with exudative age-related macular degeneration (AMD). METHODS Adults aged at least 50 years old with exudative AMD and best-corrected visual acuity (BCVA) of 73-25 Early Treatment Diabetic Retinopathy Study (ETDRS) letters were included. Patients received three monthly doses of IVT-AFL 2 mg. At week 16, patients were randomized 1:1 to IVT-AFL T&E with either 2- or 4-week adjustments. The primary endpoint was mean change in BCVA from baseline to week 52. Outcomes were assessed at weeks 52 and 96. RESULTS Baseline characteristics were comparable between the groups (n = 123 each). Over 52 weeks, mean number of injections was 7.2 and 6.9 and mean last injection interval was 10.7 and 11.8 weeks, for the 2- and 4-week groups, respectively. From baseline, mean change in BCVA was + 9.0 and + 8.4 letters (week 52) and + 7.6 and + 6.1 letters (week 96); mean change in central retinal thickness was - 134.4 µm and - 126.1 µm (week 52) and - 130.5 µm and - 125.3 µm (week 96). Last injection interval before week 52 was at least 12 weeks in 42.3% and 49.6% of patients and 56.9% and 60.2% before week 96. Over 96 weeks, mean number of injections was 10.4 (both groups). The safety profile of IVT-AFL was consistent with previous reports. CONCLUSIONS IVT-AFL administered using two different T&E regimens for treatment-naïve exudative AMD improved functional and anatomic outcomes at week 52 and outcomes were maintained to week 96. Outcomes were similar between the 2- and 4-week groups. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT02305238.
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The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial.
Campochiaro, PA, Marcus, DM, Awh, CC, Regillo, C, Adamis, AP, Bantseev, V, Chiang, Y, Ehrlich, JS, Erickson, S, Hanley, WD, et al
Ophthalmology. 2019;(8):1141-1154
Abstract
PURPOSE To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. DESIGN Phase 2, multicenter, randomized, active treatment-controlled clinical trial. PARTICIPANTS Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti-vascular endothelial growth factor intravitreal injections and were responsive to treatment. METHODS Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters, +5.0 ETDRS letters, and +3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging. CONCLUSIONS In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.
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Changes in Macular Pigment Optical Density and Serum Lutein Concentration in Japanese Subjects Taking Two Different Lutein Supplements.
Obana, A, Tanito, M, Gohto, Y, Okazaki, S, Gellermann, W, Bernstein, PS
PloS one. 2015;(10):e0139257
Abstract
PURPOSE To investigate macular pigment optical density (MPOD) and serum concentration changes of lutein in Japanese subjects participating in a clinical trial in which two formulations of lutein and zeaxanthin supplements with different physiochemical properties are used. METHODS Thirty-six healthy volunteers were recruited into this prospective, randomized, parallel-group, double-masked comparative study at a single institute. Two products were used, FloraGLO® (Kemin Japan) and XanMax® (Katra Phytochem). The lutein particle size and zeaxanthin concentrations differed between the formulations. The subjects consumed one of the two supplements for a duration of up to 6 months. MPOD levels were measured by resonance Raman spectrometry at baseline and once a month until the end of the study. Serum lutein concentration was measured at baseline, month 3, and month 6. The subjects were also tested for contrast sensitivity, glare sensitivity, visual acuity, and in addition had a focal electroretinogram measured. RESULTS The mean serum lutein concentrations increased significantly after the first three months, but the mean MPOD levels in either supplement group did not show any statistically significant increase. A detailed analysis, however, revealed three response patterns in both groups for the increase of MPOD levels and serum lutein concentration, i.e. "retinal responders", who had an increase of both MPOD levels and serum lutein concentrations (n = 13), "retinal non-responders", who had only increased serum concentrations and no change in MPOD levels (n = 20), and "retinal and serum non-responders", who had neither MPOD level nor plasma concentration increases (n = 3). The subjects with low MPOD levels at baseline appeared to show increased MPOD levels at the 6 month time point upon lutein supplementation (r = -0.4090, p = 0.0133). Glare sensitivity improved in retinal responders in both supplement groups, while there were no remarkable changes in contrast sensitivity. CONCLUSIONS No statistically significant differences could be detected for MPOD levels and serum lutein concentrations between the two investigated lutein supplement formulations. Responses to lutein supplementation regarding MPOD levels and serum lutein concentrations varied between subjects. Subjects with lower MPOD levels at baseline responded well to lutein supplementation. However, since the number of subjects was low, a further study with more subjects is needed to prove that subjects with low MPOD levels will benefit from lutein supplementation. TRIAL REGISTRATION UMIN-CTR UMIN000004593.
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Intravitreal combination of dexamethasone sodium phosphate and bevacizumab in the treatment of exudative AMD.
Vakalis, N, Echiadis, G, Pervena, A, Deligiannis, I, Kavalarakis, E, Giannikakis, S, Papaefthymiou, I
Scientific reports. 2015;:8627
Abstract
The purpose of this study is to investigate the efficacy and safety of intravitreal dexamethasone sodium phosphate (DSP) combined with bevacizumab for the treatment of neovascular age-related macular degeneration (AMD). In this non comparative case study, 30 eyes of 27 patients with CNV due to AMD received intravitreal DSP (0.2 mg) and bevacizumab (1.25 mg) during a 6-month PRN (pro re nata) dosing regimen. Visual acuity, macular thickness and intraocular pressure (IOP) were monitored and recorded. After 6 months, mean retinal thickness decreased from 423.5 ± 75.3 to 228.2 ± 34.5 and mean visual acuity improved from 0.9 ± 0.39 logMAR to 0.53 ± 0.34 (p = 0.001) logMAR. During the trial period, 81 intravitreal injections were performed in 30 eyes, thus the mean number of injections per eye was 2.7 ± 1.1. 86.7% of the eyes required 3 or less injections while only 13.3% needed 4 or more injections. None of the patients, phakic or pseudophakic, manifested an elevation of IOP during the treatment, ranging between 12 and 22 mmHg. Combined DSP and bevacizumab offers encouraging results in the challenge of AMD treatment, providing immediate response of macular edema, reduced number of intravitreal injections and stabilization or improvement of visual acuity.
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Macular pigment density at the site of altered fundus autofluorescence.
Rothenbuehler, SP, Wolf-Schnurrbusch, UE, Wolf, S
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2011;(4):499-504
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Abstract
BACKGROUND The purpose of our study was to determine whether abnormalities of increased or decreased fundus autofluorescence (FAF) are associated with local changes in macular pigment (MP) optical density in patients with age-related maculopathy (ARM) and macular degeneration (ARMD). METHODS FAF imaging and MP measurement was performed through dilated pupils using a modified confocal scanning laser ophthalmoscope (HRA, Heidelberg Engineering, Germany) according to a standard protocol. Two-wavelength autofluorescence method was employed for determination of local macular pigment optical density (LMPOD). Image analysis and measurement of LMPOD at the area of altered FAF was performed using Heidelberg Eye Explorer Software. Mean values of LMPOD at the site of FAF abnormality were compared to an adjacent location with normal background FAF of the same image. RESULTS Sixty-three eyes of 63 patients (28 male, 35 female, mean age 75.8 ± 8.8 years) were included in this analysis. Group 1 comprised 31 cases with focal increased FAF. Mean LMPOD in the area of increased FAF was 0.073 ± 0.083 compared to 0.075 ± 0.074 in the adjacent area of normal FAF. Group 2 comprised 32 cases of focal decreased FAF. Mean LMPOD in the area of decreased FAF was -0.004 ± 0.088 compared 0.053 ± 0.075 in the adjacent area of normal FAF. The site of increased FAF showed no significant difference in LMPOD (p = 0.927) compared to adjacent areas of normal FAF, while areas of decreased FAF revealed significantly lower LMPOD (p = 0.001) compared to adjacent areas of normal FAF. CONCLUSIONS Focal increases of FAF due to ARM or ARMD did not lead to change in LMPOD. Presumably, retinal layers containing MP are unaffected by these processes. For lesions exhibiting focal decreased FAF, a reduction of LMPOD cannot be excluded. Further studies are needed to investigate MP in the course of disease.
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Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13.
Clemons, TE, Kurinij, N, Sperduto, RD, ,
Archives of ophthalmology (Chicago, Ill. : 1960). 2004;(5):716-26
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OBJECTIVE To assess the association of ocular disorders and high doses of antioxidants or zinc with mortality in the Age-Related Eye Disease Study (AREDS). METHODS Baseline fundus and lens photographs were used to grade the macular and lens status of AREDS participants. Participants were randomly assigned to receive oral supplements of high-dose antioxidants, zinc, antioxidants plus zinc, or placebo. Risk of all-cause and cause-specific mortality was assessed using adjusted Cox proportional hazards models. RESULTS During median follow-up of 6.5 years, 534 (11%) of 4753 AREDS participants died. In fully adjusted models, participants with advanced age-related macular degeneration (AMD) compared with participants with few, if any, drusen had increased mortality (relative risk [RR], 1.41; 95% confidence interval [CI], 1.08-1.86). Advanced AMD was associated with cardiovascular deaths. Compared with participants having good acuity in both eyes, those with visual acuity worse than 20/40 in 1 eye had increased mortality (RR, 1.36; 95% CI, 1.12-1.65). Nuclear opacity (RR, 1.40; 95% CI, 1.12-1.75) and cataract surgery (RR, 1.55; 95% CI, 1.18-2.05) were associated with increased all-cause mortality and with cancer deaths. Participants randomly assigned to receive zinc had lower mortality than those not taking zinc (RR, 0.73; 95% CI, 0.61-0.89). CONCLUSIONS The decreased survival of AREDS participants with AMD and cataract suggests that these conditions may reflect systemic rather than only local processes. The improved survival in individuals randomly assigned to receive zinc requires further study.
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Body mass index and the incidence of visually significant age-related maculopathy in men.
Schaumberg, DA, Christen, WG, Hankinson, SE, Glynn, RJ
Archives of ophthalmology (Chicago, Ill. : 1960). 2001;(9):1259-65
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BACKGROUND Reports have suggested relationships of body weight with age-related maculopathy (ARM), particularly its nonneovascular (dry) forms, but results are inconsistent and prospective data are scarce. OBJECTIVE To examine prospectively relationships of body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) with visually significant dry and neovascular ARM during an average of 14.5 years of follow-up. METHODS Incident ARM was assessed by medical record confirmation of self-reported ARM among the 21 121 men participating in the Physicians' Health Study who (1) were followed up for at least 7 years, (2) were free of visually significant ARM at baseline, and (3) had information on BMI and cigarette smoking. We used proportional hazards regression models to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for visually significant dry ARM (256 cases) and neovascular ARM (84 cases) within 4 categories of BMI: lean (< 22.0), normal (22.0-24.9), overweight (25.0-29.9), and obese (> or = 30.0). RESULTS Adjusting for age, randomized aspirin and beta carotene assignments, and cigarette smoking, the incidence for visually significant dry ARM was lowest in men with a normal BMI. Compared with these men, the RRs (95% CIs) were as follows: 1.43 (1.01-2.04) for lean, 1.24 (0.93-1.66) for overweight, and 2.15 (1.35-3.45) for obese men. Although there was no significant relationship of BMI with the diagnosis of neovascular ARM, due to the small number of cases these analyses could not rule out an important relationship. CONCLUSIONS Obesity is a risk factor for visually significant ARM in men, in particular for dry ARM. However, the relationship of BMI with dry ARM appears to be J-shaped, and the leanest individuals also appear to be at increased risk.
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Design of Physicians' Health Study II--a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials.
Christen, WG, Gaziano, JM, Hennekens, CH
Annals of epidemiology. 2000;(2):125-34
Abstract
PURPOSE To assess the balance of benefits and risks of supplementation with beta-carotene, vitamin E, vitamin C, and multivitamins on cancer, cardiovascular (CVD), and eye diseases. DESIGN Physicians' Health Study II (PHS II) is a randomized, double-blind, placebo-controlled trial enrolling 15,000 willing and eligible physicians aged 55 years and older. PHS II will utilize a 2 x 2 x 2 x 2 factorial design to test alternate day beta-carotene, alternate day vitamin E, daily vitamin C, and a daily multivitamin, in the prevention of total and prostate cancer, CVD, and the age-related eye diseases, cataract and macular degeneration. PRIOR RESULTS The final results of the recently completed Physicians' Health Study I (PHS I), a randomized, double-blind, placebo-controlled trial in 22,071 healthy US male physicians, indicated that beta-carotene supplementation (50 mg on alternate days) had no significant benefit or harm on cancer or CVD during more than 12 years of treatment and follow-up. In regards to cancer, there were possible benefits on total and prostate cancer in those with low baseline levels assigned to beta-carotene, a finding compatible with the Chinese Cancer Prevention Study for combined treatment with beta-carotene, vitamin E, and selenium in a poorly nourished population. Further, with respect to CVD, there were apparent benefits of beta-carotene supplementation on subsequent vascular events among a small subgroup of 333 men with prior angina or revascularization. The currently available data from randomized trials of primary prevention are sparse and inconsistent for vitamin E and non-existent for vitamin C and multivitamins. For eye diseases, namely cataract and age-related macular degeneration, there are no completed large-scale randomized trials of antioxidant vitamins. CONCLUSIONS PHS II is unique in several respects. PHS II is the only primary prevention trial in apparently healthy men testing the balance of benefits and risks of vitamin E on cancer and CVD. In addition, PHS II is the only primary prevention trial in apparently healthy men to test the balance of benefits and risks of vitamin C, multivitamins, as well as any single antioxidant vitamin, alone and in combination, on cancer, CVD, and eye diseases. Finally, PHS II is the only trial testing a priori the hypotheses that beta-carotene and vitamin E may reduce the risks of prostate cancer. Thus, PHS II will add unique as well as importantly relevant and complementary information to the totality of evidence from other completed and ongoing large-scale randomized trials on the balance of benefits and risks of beta-carotene, vitamin E, vitamin C, and multivitamins alone and in combination on prevention of cancer, CVD and eye diseases.