Search

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Background/AimsTo provide longer-term data on efficacy, safety, immunogenicity and pharmacokinetics (PK) of ranibizumab biosimilar SB11 compared with the reference ranibizumab (RBZ) in patients with neovascular age-related macular degeneration (nAMD).MethodsSetting: Multicentre.Design: Randomised, double-masked, parallel-group, phase III equivalence study.Patient population: ≥50 years old participants with nAMD (n=705), one ‘study eye’. Intervention: 1:1 randomisation to monthly intravitreal injection of 0.5 mg SB11 or RBZ.Main outcome measures: Visual efficacy endpoints, safety, immunogenicity and PK up to 52 weeks.ResultsBaseline and disease characteristics were comparable between treatment groups. Of 705 randomised participants (SB11: n=351; RBZ: n=354), 634 participants (89.9%; SB11: n=307; RBZ: n=327) completed the study until week 52. Previously reported equivalence in primary efficacy remained stable up to week 52 and were comparable between SB11 and RBZ. The adjusted treatment difference between SB11 and RBZ in full analysis set at week 52 of change from baseline in best-corrected visual acuity was −0.6 letters (90% CI −2.1 to 0.9) and of change from baseline in central subfield thickness was −14.9 µm (95% CI –25.3 to –4.5). The incidence of ocular treatment-emergent adverse events (TEAEs) (SB11: 32.0% vs RBZ: 29.7%) and serious ocular TEAE (SB11: 2.9% vs RBZ: 2.3%) appeared comparable between treatment groups, and no new safety concerns were observed. The PK and immunogenicity profiles were comparable, with a 4.2% and 5.5% cumulative incidence of antidrug antibodies up to week 52 for SB11 and RBZ, respectively.ConclusionsLonger-term results of this study further support the biosimilarity established between SB11 and RBZ.

Background Despite the significant impact of retinal diseases such as wet age-related macular degeneration (wAMD) and diabetic macular edema (DME), there is a limited understanding of how these conditions are managed in Central and Eastern Europe (CEE). Objectives To provide a comprehensive overview of the clinical and economic burden of wAMD and DME in CEE and the status quo associated with their management. Methods A narrative literature review was undertaken to identify existing data on wAMD and DME, including epidemiology, economic burden, clinical guidelines, and available and reimbursed treatments. Data were collected from relevant sources such as PubMed, ophthalmology associations, national statistical offices, and government agency websites; practical viewpoints were provided by local ophthalmologists and healthcare economics experts in CEE. Results Epidemiological data on wAMD and DME are limited in CEE, and intercountry comparison is difficult because of differences in data collection methodologies. There are effective treatment options for wAMD and DME, and international guidelines advocate the use of intravitreal anti-vascular endothelial growth factor injections as first-line therapy. Local expert organizations broadly support these recommendations; nevertheless, no clinical practice guidelines exist on the treatment of wAMD and DME in CEE. Access to and reimbursement of anti-vascular endothelial growth factor agents vary significantly in the region and, as a result, many patients remain untreated or inadequately treated. Conclusions There is an urgent need for the creation of a wAMD/DME treatment program in CEE to ensure that patients have timely access to the most appropriate treatments.

Purpose: To evaluate the effect of intravitreal aflibercept injections in treatment-naive type 3 neovascularization using a fixed treatment regime during the first year of therapy. Methods: Fourteen eyes of 14 patients diagnosed with type 3 neovascularization were studied. All patients were treated with intravitreal aflibercept injections using a fixed treatment regime of 3 consecutive monthly dosages followed by 2-month interval injections. Results were assessed after a 12-month follow-up period. Changes of best corrected visual acuity (BCVA), central retinal thickness (CRT), central macular volume (CMV), and retinal pigment epithelium (RPE) atrophy at fundus autofluorescence and infrared reflectance images were recorded and analyzed. Results: BCVA improved from 60.3 ± 11.7 ETDRS letters at the baseline to 70.9 ± 10.3 ETDRS letters at 12-months follow-up (p = 0.036). Also, CRT and CMV statistically improved after the treatment (from 425 ± 117 to 308 ± 117 µm [p = 0.031] and from 9.52 ± 1.90 to 8.29 ± 0.95 mm3 [p = 0.073], respectively). In 4 patients, development and progression of RPE atrophy were observed, and it was associated with the presence of serous pigment epithelium detachment at the baseline. Furthermore, the development of a fibrotic lesion eccentric to the fovea was observed in 5 patients, without significant impairment of BCVA (p = 0.290). Conclusion: Intravitreal aflibercept administered in a fixed treatment regime during the first year of therapy may be effective for the improvement and stabilization of BCVA in eyes with type 3 neovascularization. However, RPE atrophy and subretinal/intraretinal fibrosis can develop during the treatment.

Purpose: The aim of this prospective clinical study was to evaluate the anatomical and functional results of the treatment of 54 eyes with chronic form of central serous chorioretinopathy (CSC) using photodynamic therapy in a reduced (half) verteporfin (HD-PDT) dosing regimen. Materials and Methods: Our prospective study included 54 eyes of 52 patients (40 males, 12 females) at an average age of 50.1 years (median 49.5, range 30–75 years) treated at the Ophthalmology Clinic of the First Faculty of Medicine and Military University Hospital in Prague from January 2012 to January 2018 for chronic form of CSC with a minimum disease duration of 3 months. In our study, we evaluated the improvement of the best corrected visual acuity (BCVA) and central retinal thickness (CRT) before treatment and at 1, 3, 6 and 12 months after HD-PDT. Results: The mean baseline BCVA was 68.91 ± 10.5 ETDRS letters (median 71; range 35–85) and the mean baseline CRT was 385.6 ± 118.5 µm (median 367, 5 µm; range 245–1000 µm). At the end of the follow-up period, the average BCVA was 79 ± 11 ETDRS letters (median 82; range 38–93). The improvement in BCVA before and after treatment was statistically significant in all measurements (p < 0.0001). The mean CRT at the end of the follow-up period was 263.5 ± 52 µm (median 258.5 µm; range 162–404 µm). The decrease in CRT at all timepoints was statistically significant compared to baseline (p < 0.0001). In our set of patients, at the end of the follow-up period, the retinal finding was improved or stabilized in 50 eyes (92.6 %). In this study, we observed in 2 cases the development of secondary choroidal neovascularization (CNV). Conclusion: HD-PDT is a long-term safe and effective method of treating chronic forms of CSC. However, despite a reduced dose of verteporfin, complications may occur.

Causal inference from observational data is an ambitious but highly relevant task, with diverse applications ranging from natural to social sciences. Within the scope of nonparametric time series, causal inference defined through interventions (cf. Pearl (2000)) is largely unexplored, although time order simplifies the problem substantially. We consider a marginal integration scheme for inferring causal effects from observational time series data, MINT-T (marginal integration in time series), which is an adaptation for time series of a method proposed by Ernest and B\"{u}hlmann (Electron. J. Statist, pp. 3155-3194, vol. 9, 2015) for the case of independent data. Our approach for stationary stochastic processes is fully nonparametric and, assuming no instantaneous effects consistently recovers the total causal effect of a single intervention with optimal one-dimensional nonparametric convergence rate $n^{-2/5}$ assuming regularity conditions and twice differentiability of a certain corresponding regression function. Therefore, MINT-T remains largely unaffected by the curse of dimensionality as long as smoothness conditions hold in higher dimensions and it is feasible for a large class of stationary time series, including nonlinear and multivariate processes. For the case with instantaneous effects, we provide a procedure which guards against false positive causal statements.

Purpose: To evaluate the safety and efficacy of dexamethasone intravitreal implant (Ozurdex, DEX implant) 0.7 and 0.35 mg in the treatment of patients with diabetic macular edema (DME).Design: Two randomized, multicenter, masked, sham-controlled, phase III clinical trials with identical protocols were conducted. Data were pooled for analysis.Participants: Patients (n = 1048) with DME, best-corrected visual acuity (BCVA) of 20/50 to 20/200 Snellen equivalent, and central retinal thickness (CRT) of ≥300 μm by optical coherence tomography.Methods: Patients were randomized in a 1:1:1 ratio to study treatment with DEX implant 0.7 mg, DEX implant 0.35 mg, or sham procedure and followed for 3 years (or 39 months for patients treated at month 36) at ≤40 scheduled visits. Patients who met retreatment eligibility criteria could be retreated no more often than every 6 months.Main Outcome Measures: The predefined primary efficacy endpoint for the United States Food and Drug Administration was achievement of ≥15-letter improvement in BCVA from baseline at study end. Safety measures included adverse events and intraocular pressure (IOP).Results: Mean number of treatments received over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). Mean average reduction in CRT from baseline was greater with DEX implant 0.7 mg (−111.6 μm) and DEX implant 0.35 mg (−107.9 μm) than sham (−41.9 μm; P < 0.001). Rates of cataract-related adverse events in phakic eyes were 67.9%, 64.1%, and 20.4% in the DEX implant 0.7 mg, DEX implant 0.35 mg, and sham groups, respectively. Increases in IOP were usually controlled with medication or no therapy; only 2 patients (0.6%) in the DEX implant 0.7 mg group and 1 (0.3%) in the DEX implant 0.35 mg group required trabeculectomy.Conclusions: The DEX implant 0.7 mg and 0.35 mg met the primary efficacy endpoint for improvement in BCVA. The safety profile was acceptable and consistent with previous reports.

Importance Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment. Objective To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab. Design, Setting, and Participants This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis. Interventions Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48. Main Outcomes and Measures Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of −3 letters to 3 letters for BCVA and −36 μm to 36 μm for CST. Results Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of −0.8 letter (90% CI, −1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were −108 (5) μm in the SB11 group vs −100 (5) μm in the ranibizumab group, with an adjusted treatment difference of −8 μm (95% CI, −19 to 3 μm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group. Conclusions and Relevance These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration. Trial Registration ClinicalTrials.gov Identifier:NCT03150589

We consider identifiability of partially linear additive structural equation models with Gaussian noise (PLSEMs) and estimation of distributionally equivalent models to a given PLSEM. Thereby, we also include robustness results for errors in the neighborhood of Gaussian distributions. Existing identifiability results in the framework of additive SEMs with Gaussian noise are limited to linear and nonlinear SEMs, which can be considered as special cases of PLSEMs with vanishing nonparametric or parametric part, respectively. We close the wide gap between these two special cases by providing a comprehensive theory of the identifiability of PLSEMs by means of (A) a graphical, (B) a transformational, (C) a functional and (D) a causal ordering characterization of PLSEMs that generate a given distribution P. In particular, the characterizations (C) and (D) answer the fundamental question to which extent nonlinear functions in additive SEMs with Gaussian noise restrict the set of potential causal models and hence influence the identifiability. On the basis of the transformational characterization (B) we provide a score-based estimation procedure that outputs the graphical representation (A) of the distribution equivalence class of a given PLSEM. We derive its (high-dimensional) consistency and demonstrate its performance on simulated datasets., Comment: D.R. and J.E. contributed equally to this work

We consider the problem of inferring the total causal effect of a single variable intervention on a (response) variable of interest. We propose a certain marginal integration regression technique for a very general class of potentially nonlinear structural equation models (SEMs) with known structure, or at least known superset of adjustment variables: we call the procedure S-mint regression. We easily derive that it achieves the convergence rate as for nonparametric regression: for example, single variable intervention effects can be estimated with convergence rate $n^{-2/5}$ assuming smoothness with twice differentiable functions. Our result can also be seen as a major robustness property with respect to model misspecification which goes much beyond the notion of double robustness. Furthermore, when the structure of the SEM is not known, we can estimate (the equivalence class of) the directed acyclic graph corresponding to the SEM, and then proceed by using S-mint based on these estimates. We empirically compare the S-mint regression method with more classical approaches and argue that the former is indeed more robust, more reliable and substantially simpler., 40 pages, 14 figures