We thank Gerhard Bauer and Brian Fury of the University of California at Davis Good Manufacturing Practice Laboratory for manufacturing of the investigational drug products; Jessica Munson of ARL Bio Pharma for testing the quality and stability of the investigational drugs; Henry Wang and Edward Jauch for serving as independent medical safety monitors; the members of the data and safety monitoring board (Barbara Dworetzky [chair], Gail Anderson, Jeffrey Buchhalter, Elizabeth Sugar, Alexis Topjian, and Peter Gilbert [NINDS liaison]); and especially all our patients and the emergency department nurses, pharmacists, and physicians who made the trial possible.

Survival analysis and the log-rank test will be used to compare treatment groups according to the intention-to-treat principle, including participants who require open-label anticoagulation for newly detected atrial fibrillation. Study outcomes The primary efficacy outcome is recurrent stroke of any type. The primary safety outcomes are symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage. Discussion ARCADIA is the first trial to test whether anticoagulant therapy reduces stroke recurrence in patients with atrial cardiopathy but no known atrial fibrillation.

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses.One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example. 3123 3124 GAJEWSKI ET AL.whereby individual doses are considered independent and for analysis purposes are individually compared to each other and to control. This pairwise independent model has no structure between doses. From the Bayesian framework when using a flat prior, this independent model has similar properties to several Fisher's exact tests for categorical data. 1 This lack of structure between the doses can have inefficiencies when there is smoothness to the dose-response curve. This can result in lower power for identification of the correct dose, as well as wider intervals relative to alternative model strategies. The risk of assuming a relationship is the misspecification of the model, potentially leading to poor inferences.Alternatively, with the addition of assumptions regarding the dose response relationship into the modeling framework (ie, response improves with increasing dose up to some threshold), there can be improved precision in the estimation of the efficacy at each dose, leading to better dose selection and better go/no-go decision. There are many options for the functional form of models that one can choose for inferences, including, but not limited to, EMAX, logistic, double logistic, exponential, normal dynamic linear, and quadratic. 2 While all of these models have their particular benefits and drawbacks depending on the true functional form, the EMAX model with "Hill" parameter close to 1.0 * has been shown to provide good empirical fit for designing and analyzing dose-response data across a wide range of pharmaceutical studies. 3 The impressive empiri...

BaCKgRoUND aND aIMS: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival.

There has been a renewed research interest in transcranial direct current stimulation (tDCS) as an adjunctive tool for poststroke motor recovery as it has a neuro‐modulatory effect on the human cortex. However, there are barriers towards its successful application in motor recovery as several scientific issues remain unresolved, including device‐related issues (ie, dose‐response relationship, safety and tolerability concerns, interhemispheric imbalance model, and choice of montage) and clinical trial‐related issues (ie, patient selection, timing of study, and choice of outcomes). This narrative review examines and discusses the existing challenges in using tDCS as a brain modulation tool in facilitating recovery after stroke. Potential solutions pertinent to using tDCS with the goal of harnessing the brains plasticity are proposed.

The liver has an important role in iron homeostasis through the synthesis of the serum transporter transferrin and the iron hormone hepcidin. The aim of this study was to analyze parameters of iron metabolism in a multicenter cohort of adult patients with acute liver failure (ALF) and in an acetaminophen (APAP)-induced ALF mouse model. A representative subset of 121 adults with ALF (including 66 APAP-related patients) had baseline serum samples tested for ferritin, transferrin, iron, and hepcidin. Outcomes at 3 weeks after enrollment were categorized as spontaneous survivor (SS) versus death/transplantation (NSS). Mice were assessed before (controls) and 4 and 18 hours after injection of 300 mg/kg APAP. Patients with ALF as well as APAP-treated mice displayed increased ferritin and diminished serum hepcidin and hepcidin/ferritin ratio. SS had lower iron (29.1% vs. 34.5 µmol/L; P < 0.05) and transferrin saturation (60.9% vs. 79.1%; P < 0.01), but higher hepcidin levels (8.2 vs. 2.7 ng/mL; P < 0.001) and hepcidin/ferritin ratio (0.0047 vs. 0.0009; P < 0.001) than NSS. In a multivariate analysis, a log-transformed hepcidin-containing model displayed similar prognostic power as the established Acute Liver Failure Study Group index (C-statistic 0.87 vs. 0.85) and was better than Model for End-Stage Liver Disease score (C-statistic 0.76). In mice, hepcidin levels inversely correlated with the surrogate of liver injury. Conclusion: Our findings demonstrate that several serum iron parameters significantly associate with 3-week outcomes in adults with ALF. Among them, hepcidin decreases early during experimental APAP-induced ALF, is an independent predictor and might be a useful component of future prognostic scores. (Hepatology 2019;69:2136-2149).

fibrinolytics demonstrating substantial efficacy, with combination acute therapies or expanded indications likely to be tested with much greater frequency, with the development of numerous promising restorative therapies, and with the growing efficacy of preventative therapies, incorporating a broader set of outcome assessments in stroke trials, including both global and domain-specific end points, is warranted.

BackgroundIn phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size.MethodsTo balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage.ResultsFor a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data.ConclusionsBayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.