AimsTo establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS).MethodsIn a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia.ResultsBleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13–4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose–response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity.ConclusionsDarexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial.ClinicalTrials.gov Identifier: NCT00994292

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In clinical research subjects are usually observed during a period of time. Primary and secondary endpoints are often either responses measured longitudinally over time or the time at which an event of interest occurs. Joint modeling is increasingly being used for multiple purposes such as to adjust the analysis of the longitudinal response for informative dropout mechanisms.In this paper we present %JM, a SAS macro that fits jointly generalized mixed models for longitudinal data and proportional hazards models for time-to-event responses. The macro fits normal, binary, binomial and Poisson longitudinal responses and allows choosing among a range of options to fit the trajectories of the longitudinal response over time: a linear function, splines, natural cubic splines and B-splines. For the time-to-event response, that might be right-censored, the macro fits parametric, stratified or not, proportional hazards models with the following baseline risk functions: exponential, Weibull, piecewise exponential and the generalizations of the Weibull and the Gompertz models based on splines.%JM offers several options to connect the longitudinal model and the time-to-event model: current-value-dependent and slope-dependent shared parameters, lagging effects, cumulative effects, random effects coefficients as shared parameters and interaction effects.

Background ASP8232 is a potent and specific small molecule vascular adhesion protein-1 (VAP-1) inhibitor. This study evaluated the effect of ASP8232 on excess retinal thickness when given alone or in combination with ranibizumab in patients with center-involved diabetic macular edema (CI-DME). Methods This was a phase 2a, placebo and sham-injection controlled, double-masked, randomized, parallel-group clinical trial. Participants were patients with CI-DME and central subfield thickness (CST) ≥ 375 µm in the study eye as assessed by spectral domain optical coherence tomography. Eligible patients were randomized to (1) daily oral ASP8232 40 mg monotherapy; (2) combination therapy of daily oral ASP8232 40 mg and monthly intravitreal ranibizumab 0.3 mg; or (3) monthly intravitreal ranibizumab 0.3 mg monotherapy. The treatment period was 12 weeks. CST and best corrected visual acuity (BCVA) were assessed at baseline and at Weeks 2, 4, 8, 12, 16 and 24. The primary outcome was the mean percent change from baseline in excess CST at Week 12. Secondary outcomes were BCVA, safety and tolerability, and pharmacokinetic and pharmacodynamic characteristics of ASP8232. Results After 12 weeks, the mean (95% confidence interval) percent change in excess CST was 11.4% (− 15.0%, 37.8%) in the ASP8232 group, − 61.7% (− 86.1%, − 37.2%) in the ASP8232/ranibizumab group, and − 75.3% (− 94.8%, − 55.8%) in the ranibizumab group. The change from baseline in the two ranibizumab arms was statistically significant ( P < 0.001) as was the difference between the ranibizumab groups and the ASP8232 group ( P < 0.001). Mean (SD) increase in BCVA score from baseline was 3.1 (7.3) in the ASP8232 group, 5.2 (7.1) in the ASP8232/ranibizumab group, and 8.2 (9.5) in the ranibizumab group. The increase from baseline in BCVA score was statistically and clinically significant in the ranibizumab group compared with the ASP8232 group ( P = 0.015). ASP8232 resulted in near complete inhibition of plasma VAP-1 activity whilst ranibizumab had no effect. Conclusions Near complete inhibition of plasma VAP-1 activity with ASP8232 had no effect on CST in patients with CI-DME. Furthermore, combination therapy did not provide additional benefit to treatment with ranibizumab alone, which significantly reduced CST and improved BCVA. Trial registration clinicaltrials.gov; NCT02302079. Registered on November 26, 2014 Electronic supplementary material The online version of this article (10.1186/s40942-019-0178-7) contains supplementary material, which is available to authorized users.

ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function.

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BackgroundOrthognathic surgery is the cornerstone of the treatment of dentofacial deformities, which have a great psychological and social impact on the life of the patient. Patient satisfaction and the impact on quality of life have recently become clinical parameters of growing importance. The aim of this study was to undertake a transcultural adaptation, translation to Spanish and validation of this version of the questionnaire OQLQ, used to measure quality of life in the context of Spanish culture.Material and MethodsValidation of the OQLQ questionnaire to the Spanish language was carried out through the methodology of translation and back translation, conceptual equivalence and piloting. The Spanish version was applied through a cross-sectional study to a total of 50 patients undergoing orthognathic surgery.ResultsThe adapted and validated version showed adequate metric properties of reliability, change sensitivity and validity. In this study, a positive impact of orthognathic surgery on the specific quality of life was evident in 96% of patients, with an average improvement of 58% with respect to the initial score.ConclusionsDentofacial deformities have a marked negative impact on the lives of patients, with orthognathic surgery being a therapeutic tool of great value in improving the quality of life in social, functional and aesthetic terms. The pilot test of this Spanish language version of the OQLQ proved valid for the assessment of quality of life in Spanish-speaking orthognathic patients or those with a Spanish culture. Key words:Orthognathic surgery, quality of life, validation studies, dentofacial deformities, patient satisfaction, treatment outcome.