Integrated results from the COPERNICUS and GALILEO studies.

OBJECTIVES: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO. PATIENTS AND METHODS: Patients were randomized to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept-treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52. RESULTS: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept-treated patients compared with sham, consistent with individual trial results. At week 52, after 6 months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in CONCLUSION: This analysis of integrated data from COPERNICUS and GALILEO confirmed that intravitreal aflibercept is an effective treatment for macular edema following CRVO

Impact of Baseline Retinal Nonperfusion and Macular Retinal Capillary Nonperfusion on Outcomes in the COPERNICUS and GALILEO Studies.

Purpose To evaluate the impact of baseline retinal capillary nonperfusion (RNP) and macular retinal capillary nonperfusion (MNP) status on outcomes at week 24 (W24). Design Post hoc analyses of 2 phase 3, randomized, double-masked, multicenter, sham-controlled studies. Participants Three hundred sixty-six patients with macular edema secondary to central retinal vein occlusion randomized in COPERNICUS and GALILEO. Methods We randomized patients 3:2 to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until W24. RNP and MNP were assessed by a masked independent reading center. Main Outcome Measures Proportion of patients with 10 disc areas (DA) or more of RNP and any degree of MNP at W24, relative risks of 10 DA or more of RNP or any degree of MNP at W24 developing, change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by baseline RNP and MNP status, and relationship between baseline RNP and MNP status. Results At baseline, 24.6% of patients showed 10 DA or more of RNP and 72.6% showed MNP, regardless of baseline RNP status. At W24, the pooled proportions of patients in the intravitreal aflibercept and sham groups with 10 DA or more of RNP were 11.6% and 29.0%, respectively (P = 0.0001); the respective proportions with any degree of MNP were 61.2% and 79.5% (P = 0.0008). Relative risks and 95% confidence intervals for intravitreal aflibercept versus sham were 0.4 (0.25–0.62) for 10 DA or more of RNP and 0.8 (0.68–0.90) for MNP, indicating a lower risk for these outcomes with intravitreal aflibercept than with sham. Mean BCVA change was greater in intravitreal aflibercept- versus sham-treated eyes, with less than 10 DA and 10 DA or more of RNP at baseline (+17.5 vs. +0.8 letters and +18.3 vs. −4.1 letters, respectively) and with and without baseline MNP (+15.7 vs. +0.3 letters and +17.1 vs. +0.4 letters, respectively). Agreement between baseline RNP and MNP status was low (κ = 0.12). The proportions of patients with 1 or more ocular serious adverse event in the intravitreal aflibercept- and sham-treated groups, respectively, were 3.2% and 11.3%. Conclusions At W24, visual and anatomic improvements, including perfusion status, were greater in eyes treated with intravitreal aflibercept than in eyes treated with sham, regardless of baseline RNP or MNP status

Evaluating the Impact of Intravitreal Aflibercept on Diabetic Retinopathy Progression in the VIVID-DME and VISTA-DME Studies

Purpose To evaluate the impact of intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Tarrytown, NY) versus laser on progression of diabetic retinopathy (DR) severity in Intravitreal Aflibercept Injection in Vision Impairment due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA-DME). Design Secondary and exploratory analyses of 2 phase 3, randomized, controlled studies. Participants All patients with a baseline Diabetic Retinopathy Severity Scale (DRSS) score based on fundus photograph (full analysis), patients who progressed to proliferative DR (PDR) (safety analysis) in VIVID-DME (n = 403) and VISTA-DME (n = 459), or both. Methods We randomized patients with diabetic macular edema (DME) to intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation at baseline and sham injections at every visit. Main Outcome Measures Proportions of patients with 2-step or more and 3-step or more improvements from baseline in DRSS score, who progressed to PDR, and who underwent panretinal photocoagulation (PRP). Results Among patients with an assessable baseline DRSS score, most showed moderately severe or severe nonproliferative DR. The proportions of patients treated with 2q4, 2q8, and laser with a 2-step or more improvement in DRSS score at week 100 were 29.3%, 32.6%, and 8.2%, respectively, in VIVID-DME and 37.0%, 37.1%, and 15.6%, respectively, in VISTA-DME; the proportions with a 3-step or more improvement in DRSS score were 7.3%, 2.3%, and 0%, respectively, and 22.7%, 19.9%, and 5.2%, respectively. Fewer patients in the 2q4 and 2q8 groups versus the laser group progressed to PDR at week 100 in VISTA-DME (1.5% and 2.2% vs. 5.3%) and VIVID-DME (3.2% and 2.0% vs. 12.3%). The proportions of patients who underwent PRP were 2.9%, 0.7%, and 4.5%, respectively, in VIVID-DME and 1.9%, 0.7%, and 5.2%, respectively, in VISTA-DME. The most frequent serious ocular adverse event at week 100 was cataract (pooled intravitreal aflibercept, 1.7% of patients; laser, 3.5% of patients). Conclusions These analyses demonstrate the benefit of intravitreal aflibercept over laser with respect to DR progression, suggesting a benefit on DME, and on underlying DR

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

Observation of an Excited Bc+ State

Using pp collision data corresponding to an integrated luminosity of 8.5 fb-1 recorded by the LHCb experiment at center-of-mass energies of s=7, 8, and 13 TeV, the observation of an excited Bc+ state in the Bc+π+π- invariant-mass spectrum is reported. The observed peak has a mass of 6841.2±0.6(stat)±0.1(syst)±0.8(Bc+) MeV/c2, where the last uncertainty is due to the limited knowledge of the Bc+ mass. It is consistent with expectations of the Bc∗(2S31)+ state reconstructed without the low-energy photon from the Bc∗(1S31)+→Bc+γ decay following Bc∗(2S31)+→Bc∗(1S31)+π+π-. A second state is seen with a global (local) statistical significance of 2.2σ (3.2σ) and a mass of 6872.1±1.3(stat)±0.1(syst)±0.8(Bc+) MeV/c2, and is consistent with the Bc(2S10)+ state. These mass measurements are the most precise to date

Measurement of the inelastic pp cross-section at a centre-of-mass energy of 13TeV

The cross-section for inelastic proton-proton collisions at a centre-of-mass energy of 13TeV is measured with the LHCb detector. The fiducial cross-section for inelastic interactions producing at least one prompt long-lived charged particle with momentum p > 2 GeV/c in the pseudorapidity range 2 < η < 5 is determined to be ϭ acc = 62:2 ± 0:2 ± 2:5mb. The first uncertainty is the intrinsic systematic uncertainty of the measurement, the second is due to the uncertainty on the integrated luminosity. The statistical uncertainty is negligible. Extrapolation to full phase space yields the total inelastic proton-proton cross-section ϭ inel = 75:4 ± 3:0 ± 4:5mb, where the first uncertainty is experimental and the second due to the extrapolation. An updated value of the inelastic cross-section at a centre-of-mass energy of 7TeV is also reported

Updated Determination of D⁰–D¯⁰Mixing and CP Violation Parameters with D⁰→K⁺π⁻ Decays

We report measurements of charm-mixing parameters based on the decay-time-dependent ratio of D⁰→K⁺π⁻ to D⁰→K⁻π⁺ rates. The analysis uses a data sample of proton-proton collisions corresponding to an integrated luminosity of 5.0  fb⁻¹ recorded by the LHCb experiment from 2011 through 2016. Assuming charge-parity (CP) symmetry, the mixing parameters are determined to be x′²=(3.9±2.7)×10⁻⁵, y′=(5.28±0.52)×10⁻³, and R[subscript D]=(3.454±0.031)×10⁻³. Without this assumption, the measurement is performed separately for D⁰ and D[over ¯]⁰ mesons, yielding a direct CP-violating asymmetry A[subscript D]=(-0.1±9.1)×10⁻³, and magnitude of the ratio of mixing parameters 1.00<|q/p|<1.35 at the 68.3% confidence level. All results include statistical and systematic uncertainties and improve significantly upon previous single-measurement determinations. No evidence for CP violation in charm mixing is observed

Measurement of CP observables in B± → D(⁎)K± and B± → D(⁎)π± decays

Measurements of CP observables in B ± →D (⁎) K ± and B ± →D (⁎) π ± decays are presented, where D (⁎) indicates a neutral D or D ⁎ meson that is an admixture of D (⁎)0 and D¯ (⁎)0 states. Decays of the D ⁎ meson to the Dπ 0 and Dγ final states are partially reconstructed without inclusion of the neutral pion or photon, resulting in distinctive shapes in the B candidate invariant mass distribution. Decays of the D meson are fully reconstructed in the K ± π ∓ , K + K − and π + π − final states. The analysis uses a sample of charged B mesons produced in pp collisions collected by the LHCb experiment, corresponding to an integrated luminosity of 2.0, 1.0 and 2.0 fb −1 taken at centre-of-mass energies of s=7, 8 and 13 TeV, respectively. The study of B ± →D ⁎ K ± and B ± →D ⁎ π ± decays using a partial reconstruction method is the first of its kind, while the measurement of B ± →DK ± and B ± →Dπ ± decays is an update of previous LHCb measurements. The B ± →DK ± results are the most precise to date

Observation of D⁰ Meson Decays to Π⁺π⁻μ⁺μ⁻ and K⁺K⁻μ⁺μ⁻ Final States

The first observation of the D⁰→π⁺π⁻μ⁺μ⁻ and D⁰→K⁺K⁻μ⁺μ⁻ decays is reported using a sample of proton-proton collisions collected by LHCb at a center-of-mass energy of 8 TeV, and corresponding to 2  fb⁻¹ of integrated luminosity. The corresponding branching fractions are measured using as normalization the decay D⁰→K⁻π⁺[μ⁺μ⁻][subscript ρ⁰/ω], where the two muons are consistent with coming from the decay of a ρ⁰ or ω meson. The results are B(D⁰→π⁺π⁻μ⁺μ⁻)=(9.64±0.48±0.51±0.97)×10⁻⁷ and B(D⁰→K⁺K⁻μ⁺μ⁻)=(1.54±0.27±0.09±0.16)×10⁻⁷, where the uncertainties are statistical, systematic, and due to the limited knowledge of the normalization branching fraction. The dependence of the branching fraction on the dimuon mass is also investigated

Measurement of branching fractions of charmless four-body Λ_b ⁰ and Ξ_b ⁰ decays

A search for charmless four-body decays of Λb 0 and Ξb 0 baryons with a proton and three charged mesons (either kaons or pions) in the final state is performed. The data sample used was recorded in 2011 and 2012 with the LHCb experiment and corresponds to an integrated luminosity of 3 fb−1. Six decay modes are observed, among which Λb 0 → pK−π+π−,Λb 0 → pK−K+K−,Ξb 0 → pK−π+π− and Ξb 0 → pK−π+K− are established for the first time. Their branching fractions (including the ratio of hadronisation fractions in the case of the Ξb 0 baryon) are determined relative to the Λb 0 → Λc +π− decay.[Figure not available: see fulltext.].</p