Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study.

PURPOSE: To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). DESIGN: AQUA was a multicenter, open-label, single-arm, phase 4 study. PARTICIPANTS: Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. METHODS: Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. MAIN OUTCOME MEASURES: The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. RESULTS: A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 µm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was -175.38 µm (SD, 132.62 µm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. CONCLUSIONS: Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.

EFFICACY AND SAFETY OUTCOMES OF INTRAVITREAL AFLIBERCEPT FOCUSING ON PATIENTS WITH DIABETIC MACULAR EDEMA FROM JAPAN.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept injection (IAI) in Japanese patients with diabetic macular edema (DME). METHODS: VIVID-DME was a Phase 3 study comprising patients with DME randomized 1:1:1 to IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 4 weeks until Week 16 then 8-week dosing (2q8), and laser. A total of 403 patients (76 Japanese) were included in this study. VIVID-Japan (72; all Japanese patients) was a nonrandomized, open-label study comprising Japanese patients with DME receiving IAI 2q4 until Week 16, then 2q8. Primary efficacy endpoint (Week 52) of VIVID-DME was mean change from baseline in best-corrected visual acuity; VIVID-Japan evaluated safety and tolerability. RESULTS: Mean change in best-corrected visual acuity (letters) for 2q4, 2q8, and laser groups was +10.6, +10.9, and +1.2 and +9.8, +9.5, and +1.1 in the non-Japanese and Japanese populations of VIVID-DME, respectively. In VIVID-Japan, it was +9.3 for IAI 2q8. Intravitreal aflibercept injection also provided consistently greater benefits for anatomical outcomes versus laser. Adverse events were consistent with the known safety profile of IAI. CONCLUSION: In Japanese patients with DME, IAI treatment was superior to laser for visual and anatomical outcomes and resulted in efficacy and safety outcomes similar to those in a non-Japanese patient population.

EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT AND RANIBIZUMAB IN ASIAN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Subgroup Analyses From the VIEW Trials.

PURPOSE: To assess the treatment effect of intravitreal aflibercept and ranibizumab in Asian patients with neovascular age-related macular degeneration. METHODS: We evaluated data from VIEW 1 and VIEW 2, comparing functional and morphologic outcomes at Week 96 between intravitreal aflibercept 2 mg monthly (2q4) or 2 mg bimonthly after 3 initial monthly doses (2q8) versus ranibizumab 0.5 mg monthly among Asian patients (n = 269) and between Asian and white patients (n = 2044). RESULTS: In Asian patients, there were no significant differences between intravitreal aflibercept 2q4 and 2q8 compared with ranibizumab in mean gain in best-corrected visual acuity (10.23 and 8.35 vs. 8.51 letters). Reduction in central retinal thickness was greater for intravitreal aflibercept 2q4 (150.43 µm, P = 0.0075) and 2q8 (148.15 µm, P = 0.0126) than ranibizumab (119.46 µm). The proportion of dry retinas was greater for intravitreal aflibercept 2q4 (65.7%, P < 0.01) than ranibizumab (41.7%). There were no differences in outcomes between Asian and white patients. Serious treatment-emergent ocular adverse events occurred in <8% of treated eyes, evenly distributed across subgroups. CONCLUSION: In Asian patients with neovascular age-related macular degeneration, functional and morphologic outcomes were largely similar between intravitreal aflibercept and ranibizumab groups, and to results seen in white patients.

Intravitreal aflibercept versus photodynamic therapy in Chinese patients with neovascular age-related macular degeneration: outcomes of the SIGHT study / 中华眼底病杂志

Objective To assess the efficacy and safety ofintravitreal aflibercept injection (IAI) compared with photodynamic therapy (PDT) in the treatment of Chinese patients with predominantly classic subfoveal choroidal neovascularization (CNV) lesions secondary to neovascular age-related macular degeneration (nAMD).Methods A randomized,double-blind,multi-center phase-3 clinical trial lasting for 52weeks (from December 2011 to August 2014).Subjects were randomized in a 3:1 ratio to either IAI group or PDT-to-IAI group.Subjects in the IAI group received 2 mg IAI at baseline and at week 4,8,16,24,32,40,48,with sham injection at week 28,36.Subjects in the PDT-to-IAI group were forced to receive PDT once at baseline and more time at week 12,24 if PDT retreatment conditions were met.Sham injections were given in PDT-to-IAI group at baseline and at week 4,8,16 and 24,followed by 2 mg IAI at week 28,32,36,40,48.The primary outcome of efficacy were the change in mean Best Corrected Visual Acuity (BCVA) from baseline to week 28,and that of week 52.Safety evaluation included the percentage of subjects who suffered treatment emergent adverse events (TEAEs).Results Among the 304 subjects enrolled,there were 228 and 76 cases in IAI group and PDT-to-IAI group respectively.At week 28,the changes of mean BCVA in IAI group,PDT-to-IAI group compared to baseline were +14.0,+3.9 letters,respectively.At week 52,the changes of mean BCVA in two groups were + 15.2,+8.9 letters respectively with the difference of +6.2 letters (95％CI 2.6-9.9,P=0.000 9).At week 52,the mean foveal retinal thickness in the two groups decreased by-189.6,-170.0 μm,respectively.Subjects with the most BCVA increase in IAI group were those aged ＜65,and those with active CNV lesion area ＜50％ of total lesion area.The most common TEAEs in IAI group and PDT-to-IAI group are macular fibrosis [11.8％ (27/228),6.6％ (5/76)] and BCVA decline [6.6％ (15/228),21.1％ (16/76)].There were 3 cases of arterial thromboembolic events defined in the antiplatelet experimental collaboration group,but all were considered unrelated to interventions.Conclusions The efficacy of aflibercept is superior to that of PDT in nAMD patients in China.The therapeutic effect of aflibercept persisted to week 52 in all subjects.The rate of adverse events was consistent with the safety data of aflibercept known before.

Predictors of visual outcomes in patients with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapy: post hoc analysis of the VIEW studies.

PURPOSE: Identify predictors for response to anti-vascular endothelial growth factor (VEGF) therapy in patients with neovascular (wet) age-related macular degeneration (nAMD). METHODS: Retrospective, post hoc analysis of VIEW 1/2. Patients were randomized 1:1:1:1 to 0.5 mg intravitreal aflibercept (IVT-AFL) injection every 4 weeks (0.5q4); 2 mg IVT-AFL every 4 weeks (2q4); 2 mg IVT-AFL every 8 weeks (2q8) after an initial three injections at weeks 0, 4 and 8 or 0.5 mg intravitreal ranibizumab every 4 weeks (0.5q4). RESULTS: 1815 patients [IVT-AFL 2q4 (n = 613); IVT-AFL 2q8 (n = 607); ranibizumab 0.5q4 (n = 595)] were included. Baseline demographics/characteristics were evenly balanced. Younger age (49-69 years), lower visual acuity (VA) [10.0-≤45.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and smaller choroidal neovascularization (CNV) size [0.0-≤3.1 disc areas (DA)] at baseline were associated with the most vision gain (≥15 letters) over 52 weeks (all nominal p < 0.0001).Younger age, higher baseline VA (>64.0-≤83.0 letters) and smaller CNV size were associated with a VA ≥20/40 at week 52. Predominantly classic CNV at baseline (nominal p = 0.0007), older age (≥90 years), lower baseline VA (10.0-≤ 45.0 ETDRS letters) and larger CNV size (>10.1-≤32.6 DA) were all associated with a VA ≤20/200 at week 52 (all nominal p < 0.0001). Along with treatment (nominal p < 0.0001), lower VA (p = 0.0166) and smaller central retinal thickness (both nominal p = 0.0190) were predictors for dry retina development. CONCLUSION: Younger age, lower VA and smaller CNV size at baseline were all associated with greater vision gains over 52 weeks while younger age, higher VA and smaller CNV size at treatment start were more likely to achieve best-corrected VA 20/40 or better after a year's treatment, suggesting the benefit of early anti-VEGF treatment.

Evaluating the Relationship Between Visual Acuity and Utilities in Patients With Diabetic Macular Edema Enrolled in Intravitreal Aflibercept Studies.

Purpose: The purpose of this study was to explore the relationship between visual acuity and utility (health-related quality of life) in diabetic macular edema (DME) using intravitreal aflibercept data. Methods: The relationship between visual acuity in the best-seeing eye (BSE) and worse-seeing eye (WSE) and utility was explored using ordinary least squares (OLS) and random-effects models adjusted for different covariates (age, age2, sex, body mass index, smoking status, glycated hemoglobin, diabetes severity, comorbidities, and geographic region). Utility was measured using the EuroQoL-five dimensions questionnaire (EQ-5D) and Visual Functioning Questionnaire-Utility Index (VFQ-UI). For each model, coefficients (R2) were reported, and WSE/BSE was expressed as the ratio of coefficients (OLS models). Models were independent of treatment effects, and outcomes from all time points (up to week 100) were included where available. Results: Data from 1320 patients with DME were analyzed. In all models, the association between visual acuity (BSE > WSE) was stronger with VFQ-UI- than EQ-5D-derived utilities. The estimated relationship between VFQ-UI and visual acuity in the BSE and WSE was robust, even with an increasing number of covariates. WSE/BSE coefficient ratios were similar across VFQ-UI OLS models (32%) compared with EQ-5D models (41%-48%). Actual (unadjusted) versus predicted data plots also showed a better fit with VFQ-UI- than EQ-5D-derived utilities. Conclusions: These analyses show that VFQ-UI was more sensitive than EQ-5D-derived utilities for measuring the impact of visual acuity in the BSE and WSE. Visual acuity in the BSE was a major contributor to utility, but WSE is also important though to a lesser degree as shown by the coefficient ratios. These new data will be useful for health technology assessments in DME, where utilities data are lacking.

Baseline Characteristics of the Fellow Eye in Patients with Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of the VIEW Studies.

PURPOSE: The aim was to describe baseline characteristics of the fellow eye of patients with neovascular age-related macular degeneration (nAMD). METHODS: A pooled, post hoc analysis of patients with nAMD enrolled in the VIEW studies was carried out. The VIEW studies compared intravitreal aflibercept (monthly or every 2 months after 3 monthly injections) with monthly ranibizumab. Baseline choroidal neovascularization (CNV) status of fellow eyes and baseline best-corrected visual acuity (BCVA) and lens status of all eyes were evaluated. Additional analyses evaluated the presence of drusen and pigment in fellow eyes. RESULTS: When comparing both eyes, baseline BCVA was worse in 23.8% of fellow eyes and in 75.2% of study eyes. Lens status of fellow eyes and study eyes was similar. Baseline visual acuity of the study eye and that of the fellow eye were not correlated. Most fellow eyes had signs of early AMD, with 34.6% (n = 843) of fellow eyes having evidence of scarring. CONCLUSIONS: In patients in the VIEW studies, most fellow eyes had evidence of AMD, highlighting the importance of examining both eyes, with close follow-up thereafter, in order to detect and treat CNV earlier as needed.

Betaferon in chronic viral cardiomyopathy (BICC) trial: Effects of interferon-ß treatment in patients with chronic viral cardiomyopathy.

BACKGROUND: Chronic viral infections of the heart are considered one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus- or immune-mediated myocardial injury. Symptomatic treatment does not influence the viral cause of heart failure, and the effect of antiviral treatment has not been determined, yet. METHODS AND RESULTS: In this phase II study 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus (EV), adenovirus, and/or parvovirus B19 genomes in their myocardial tissue were randomly assigned to double-blind treatment, and received either placebo (n = 48) or 4 × 10(6) (n = 49) and 8 × 10(6) IU (n = 46) interferon beta-1b (IFN-ß-1b) for 24 weeks, in addition to standard heart failure treatment. Patients with active myocarditis or other specific causes of heart failure were excluded. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-ß-1b groups (odds ratio 2.33, p = 0.048), similarly in both interferon groups and both strata. IFN-ß-1b treatment was associated with favourable effects on NYHA functional class (p = 0.013 at follow-up week 12), improvement in quality of life (Minnesota Heart Failure score; p = 0.032 at follow-up week 24) and patient global assessment (follow-up week 12 to follow-up week 24; p = 0.039). The frequency of adverse cardiac events was not higher in the IFN-ß-1b groups compared to the placebo group. CONCLUSIONS: Immunomodulatory IFN-ß-1b treatment is a well-tolerated and safe treatment option, leading to effective virus clearance or reduction of the virus load in patients with chronic viral cardiomyopathy. Favourable clinical effects assess quality of life, NYHA functional class, and patient global assessment. ClinicalTrials.gov identifier: NCT001185250.

Efficacy and safety of intravitreal aflibercept injection in wet age-related macular degeneration: outcomes in the Japanese subgroup of the VIEW 2 study.

BACKGROUND/AIMS: To evaluate efficacy and safety of intravitreal aflibercept (IVT-AFL) in Japanese patients with wet age-related macular degeneration (wAMD) from the VIEW 2 trial. METHODS: In this double-masked study, patients were randomised to: 0.5 mg IVT-AFL every 4 weeks (0.5q4); 2 mg IVT-AFL every 4 weeks (2q4); 2 mg IVT-AFL every 8 weeks (2q8) after 3 monthly injections; or 0.5 mg ranibizumab every 4 weeks (Rq4). Main efficacy outcomes included vision maintenance and best-corrected visual acuity (BCVA) at week 52. RESULTS: At week 52, all Japanese patients in the IVT-AFL groups (n=70) maintained vision, compared with 96% of Japanese patients (n=23/24) treated with ranibizumab. Japanese patients in all treatment groups showed improvement in BCVA after treatment. The Rq4, 2q4 and 2q8 groups experienced similar gains in BCVA from baseline. The 0.5q4 group had higher gains due to an unexpected drop in BCVA between screening and baseline. Central retinal thickness and mean area of choroidal neovascularisation decreased in all treatment groups with similar magnitude. Ocular treatment-emergent adverse events were balanced across treatment groups. CONCLUSIONS: IVT-AFL was effective and well tolerated in Japanese patients. Outcomes in this population were consistent with those in the overall VIEW 2 population. TRIAL REGISTRATION NUMBER: NCT00637377.

Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.

PURPOSE: To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period. DESIGN: Two randomized, double-masked, active-controlled, phase 3 trials. PARTICIPANTS: Two thousand four hundred fifty-seven patients with neovascular AMD. METHODS: From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES: Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA. RESULTS: Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of -0.64 [95% CI, -0.89 to -0.40] and -0.55 [95% CI, -0.79 to -0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week 96. CONCLUSIONS: All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.