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Clinical trial simulation

Matthew A Psioda, Joseph G Ibrahim
We consider the problem of Bayesian sample size determination for a clinical trial in the presence of historical data that inform the treatment effect. Our broadly applicable, simulation-based methodology provides a framework for calibrating the informativeness of a prior while simultaneously identifying the minimum sample size required for a new trial such that the overall design has appropriate power to detect a non-null treatment effect and reasonable type I error control. We develop a comprehensive strategy for eliciting null and alternative sampling prior distributions which are used to define Bayesian generalizations of the traditional notions of type I error control and power...
March 14, 2018: Biostatistics
Débora Finger, Fábio Juner Lanferdini, Juliano Boufleur Farinha, Clarissa Müller Brusco, Lucas Helal, Francesco Pinto Boeno, Eduardo Lusa Cadore, Ronei Silveira Pinto
INTRODUCTION: Protein (PRO) combined with a carbohydrate (CHO) beverage may have an ergogenic effect on endurance performance. However, evidence regarding its efficacy on similar conditions to athletes' race day is still lacking. OBJECTIVE: To compare the effect of three different nutritional supplementation strategies on performance and muscle recovery in a duathlon protocol. METHODS: , 13 male athletes (29.7 ± 7.7 years) participated in three simulated Olympic-distance duathlons under three different, randomly assigned, supplementation regimens: carbohydrate drink (CHO, 75 g); isocaloric CHO plus protein drink (CHO+PRO, 60...
March 15, 2018: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Akhil Kumar, Ashish Tiwari, Ashok Sharma
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target...
March 15, 2018: Current Neuropharmacology
Catriona Crossan, Hakim-Moulay Dehbi, Hilarie Williams, Neil Poulter, Anthony Rodgers, Stephen Jan, Simon Thom, Joanne Lord
INTRODUCTION: The 'Use of a Multi-drug Pill in Reducing cardiovascular Events' (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data...
March 14, 2018: BMJ Open
Inès Daguet, Kayla Bergeron-Vézina, Marie-Philippe Harvey, Marylie Martel, Guillaume Léonard
Purpose: Placebo analgesia refers to a perceived reduction in pain intensity following the administration of a simulated or otherwise medically ineffective treatment. Previous studies have shown that many factors can influence the magnitude of placebo analgesia. However, few investigations have examined the effect of age on placebo analgesia, and none have done it in the context of electrotherapeutic interventions. The objective of this study is to compare the placebo response induced by sham transcutaneous electrical nerve stimulation (TENS) between young and older individuals, using an experimental heat-pain paradigm...
2018: Clinical Interventions in Aging
Simone A Dijkland, Daphne C Voormolen, Esmee Venema, Bob Roozenbeek, Suzanne Polinder, Juanita A Haagsma, Daan Nieboer, Vicky Chalos, Albert J Yoo, Jennifer Schreuders, Aad van der Lugt, Charles B L M Majoie, Yvo B W E M Roos, Wim H van Zwam, Robert J van Oostenbrugge, Ewout W Steyerberg, Diederik W J Dippel, Hester F Lingsma
BACKGROUND AND PURPOSE: The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a new patient-centered primary outcome in stroke trials. We aimed to describe utility weights for the mRS health states and to evaluate the statistical efficiency of the UW-mRS to detect treatment effects in stroke intervention trials. METHODS: We used data of the 500 patients enrolled in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands)...
March 13, 2018: Stroke; a Journal of Cerebral Circulation
Thomas M Braun
In contrast with typical Phase III clinical trials, there is little existing methodology for determining the appropriate numbers of patients to enroll in adaptive Phase I trials. And, as stated by Dennis Lindley in a more general context, "[t]he simple practical question of 'What size of sample should I take' is often posed to a statistician, and it is a question that is embarrassingly difficult to answer." Historically, simulation has been the primary option for determining sample sizes for adaptive Phase I trials, and although useful, can be problematic and time-consuming when a sample size is needed relatively quickly...
March 13, 2018: Biometrics
Michael J Martens, Brent R Logan
Competing risks endpoints arise when patients can fail therapy from several causes. Analyzing these outcomes allows one to assess directly the benefit of treatment on a primary cause of failure in a clinical trial setting. Regression models can be used in clinical trials to adjust for residual imbalances in patient characteristics, improving the power to detect treatment differences. But, none of the competing risks methods currently available for use in group sequential trials adjust for covariates. We propose a group sequential test for treatment effect that, because it is based on the Fine-Gray model, permits adjustment for covariates...
March 13, 2018: Biometrics
Richard C Mather, Shane J Nho, Andrew Federer, Berna Demiralp, Jennifer Nguyen, Asha Saavoss, Michael J Salata, Marc J Philippon, Asheesh Bedi, Christopher M Larson, J W Thomas Byrd, Lane Koenig
BACKGROUND: The diagnosis and treatment of femoroacetabular impingement (FAI) have increased steadily within the past decade, and research indicates clinically significant improvements after treatment of FAI with hip arthroscopy. PURPOSE: This study examined the societal and economic impact of hip arthroscopy by high-volume surgeons for patients with FAI syndrome aged <50 years with noncontroversial diagnosis and indications for surgery. STUDY DESIGN: Economic and decision analysis; Level of evidence, 2...
March 1, 2018: American Journal of Sports Medicine
Johanna Mielke, Heinz Schmidli, Byron Jones
For the approval of biosimilars, it is, in most cases, necessary to conduct large Phase III clinical trials in patients to convince the regulatory authorities that the product is comparable in terms of efficacy and safety to the originator product. As the originator product has already been studied in several trials beforehand, it seems natural to include this historical information into the showing of equivalent efficacy. Since all studies for the regulatory approval of biosimilars are confirmatory studies, it is required that the statistical approach has reasonable frequentist properties, most importantly, that the Type I error rate is controlled-at least in all scenarios that are realistic in practice...
March 13, 2018: Biometrical Journal. Biometrische Zeitschrift
Ronald W Gimbel, Ronald G Pirrallo, Steven C Lowe, David W Wright, Lu Zhang, Min-Jae Woo, Paul Fontelo, Fang Liu, Zachary Connor
BACKGROUND: The frequency of head computed tomography (CT) imaging for mild head trauma patients has raised safety and cost concerns. Validated clinical decision rules exist in the published literature and on-line sources to guide medical image ordering but are often not used by emergency department (ED) clinicians. Using simulation, we explored whether the presentation of a clinical decision rule (i.e. Canadian CT Head Rule - CCHR), findings from malpractice cases related to clinicians not ordering CT imaging in mild head trauma cases, and estimated patient out-of-pocket cost might influence clinician brain CT ordering...
March 12, 2018: BMC Medical Informatics and Decision Making
Joseph J Kavolus, David Sia, Hollis G Potter, David E Attarian, Paul F Lachiewicz
BACKGROUND: Surgeon-performed periarticular injections and anesthesiologist-performed femoral nerve or adductor canal blocks with local anesthetic are in common use as part of multimodal pain management regimens for patients undergoing TKA. However, femoral nerve blocks risk causing quadriceps weakness and falls, and anesthesiologist-performed adductor canal blocks are costly in time and resources and may be unreliable. We investigated the feasibility of a surgeon-performed saphenous nerve ("adductor canal") block from within the knee at the time of TKA...
January 2018: Clinical Orthopaedics and related Research
Xiaolei Xie, Tianhua He, Jian Kang, David S Siscovick, Yan Li, José A Pagán
China has the largest population of adults with hypertension in the world. Recent clinical trials have shown that intensive hypertension control can help patients achieve lower blood pressure and reduce the incidence of major cardiovascular disease (CVD) events, but this level of hypertension control also incurs additional costs to patients and society and may result in a substantial increase in adverse events. The objective of this study is to assess the cost-effectiveness of intensive hypertension control to inform health policymakers and health care delivery systems in China in their decision-making regarding hypertension treatment strategies...
March 8, 2018: Preventive Medicine
Christian Dualé, Jean-Michel Cardot, Fabienne Joanny, Anna Trzeciakiewicz, Elodie Martin, Gisèle Pickering, Claude Dubray
While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag®, was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element)...
March 9, 2018: Biological Trace Element Research
Sinan Şen, Ralf Erber, Kevin Kunzmann, Stefanie Kirschner, Vanessa Weyer, Lothar Schilling, Marc A Brockmann, Stefan Rues, Gül Orhan, Christopher J Lux, Sebastian Zingler
OBJECTIVE: Optical coherence tomography (OCT) is a clinical standard in ophthalmology. Currently, its application in dentistry is gaining increasing interest. In this study, we tested the possibility to use a modified commercially available spectral domain OCT (SD-OCT) to assess the layer thickness of orthodontic surface sealants. MATERIALS AND METHODS: Reference samples of surface sealants for calibration and repeatability testing were measured using a micrometer screw...
March 9, 2018: Clinical Oral Investigations
Yuming Wang, Lijun Li, Jun Fan, Yang Dai, Alan Jiang, Mei-Yu Geng, Jing Ai, Wenhu Duan
Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2)...
March 9, 2018: Journal of Medicinal Chemistry
Xu Steven Xu, Min Yuan, Hao Zhu, Yaning Yang, Hui Wang, Honghui Zhou, Jinfeng Xu, Liping Zhang, Jose Pinheiro
OBJECTIVE: To clarify the hypothesis tests associated with the full covariate modeling (FCM) approach in population pharmacokinetic (PPK) analysis, investigate the potential impact of multiplicity in PPK analysis, and evaluate simultaneous confidence intervals (SCI) as an approach to control multiplicity. METHODS: Clinical trial simulations were performed using a simple one-compartment PK model. Different numbers of covariates, sample sizes, effect sizes of covariates, and correlations among covariates were explored...
March 9, 2018: British Journal of Clinical Pharmacology
Dawen Kou, Chen Zhang, Hiuwing Yiu, Tania Ng, Joseph W Lubach, Matthew Janson, Chen Mao, Matthew Durk, Leslie Chinn, Helen Winter, Larry Wigman, Peter Yehl
In this study, a multi-pronged approach of in vitro experiments, in silico simulations, and in vivo studies was developed to evaluate the dissolution, supersaturation, precipitation, and absorption of three formulations of Compound-A, a BCS Class 2 weak base with pH-dependent solubility. In in vitro 2-stage dissolution experiments, the solutions were highly supersaturated with no precipitation at the low dose but increasing precipitation at higher doses. No difference in precipitation was observed between the capsules and tablets...
March 9, 2018: Molecular Pharmaceutics
Tingting Fu, Guoxun Zheng, Gao Tu, Fengyuan Yang, Yu Zong Chen, Xiaojun Yao, Xiaofeng Li, Weiwei Xue, Feng Zhu
Metabotropic glutamate receptor 5 (mGlu5) plays a key role in synaptic information storage and memory, which is a well-known target for a variety of psychiatric and neurodegenerative disorders. In recent years, the increasing efforts have been focused on the design of allosteric modulators, and the negative allosteric modulators (NAMs) are the front runners. Recently, the architecture of transmembrane (TM) domain of mGlu5 receptor has been determined by crystallographic experiment. However, it has been not well understood how the pharmacophores of NAMs accommodated into the allosteric binding site...
March 9, 2018: ACS Chemical Neuroscience
Sofía S Villar
In a rare life-threatening disease setting the number of patients in the trial is a high proportion of all patients with the condition (if not all of them). Further, this number is usually not enough to guarantee the required statistical power to detect a treatment effect of a meaningful size. In such a context, the idea of prioritizing patient benefit over hypothesis testing as the goal of the trial can lead to a trial design that produces useful information to guide treatment, even if it does not do so with the standard levels of statistical confidence...
April 2018: Probability in the Engineering and Informational Sciences
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