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.