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.
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.
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...
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.
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