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Clinical trial simulation

Andrea Callegaro, Bart Spiessens, Benjamin Dizier, Fernando U Montoya, Hans C van Houwelingen
In this paper, we considered different methods to test the interaction between treatment and a potentially large number (p) of covariates in randomized clinical trials. The simplest approach was to fit univariate (marginal) models and to combine the univariate statistics or p-values (e.g., minimum p-value). Another possibility was to reduce the dimension of the covariates using the principal components (PCs) and to test the interaction between treatment and PCs. Finally, we considered the Goeman global test applied to the high-dimensional interaction matrix, adjusted for the main (treatment and covariates) effects...
October 20, 2016: Biometrical Journal. Biometrische Zeitschrift
V R Knight-Schrijver, V Chelliah, L Cucurull-Sanchez, N Le Novère
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response...
2016: Computational and Structural Biotechnology Journal
Satoshi Nagase, Tomokazu Iyoda, Hiroshi Kanno, Tomohide Akase, Ichiro Arakawa, Tadao Inoue, Yoshio Uetsuka
Phase III clinical trials have comfirmed that the S-1 plus oxaliplatin(SOX)is inferior to the capecitabine plus oxaliplatin (COX)regimen in the treatment of metastatic colorectal cancer.On the basis of these findings, we compared, using a clinical decision analysis-based approach, the cost-effectiveness of the SOX and COX regimens.Herein, we simulated the expected effects and costs of the SOX and COX regimens using the markov model.Clinical data were obtained from Hong's 2012 report.The cost data comprised the costs for pharmacist labor, material, inspection, and treatment for adverse event, as well as the total cost of care at the advanced stage...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Wolfgang G Kunz, M G Myriam Hunink, Wieland H Sommer, Sebastian E Beyer, Felix G Meinel, Franziska Dorn, Stefan Wirth, Maximilian F Reiser, Birgit Ertl-Wagner, Kolja M Thierfelder
BACKGROUND AND PURPOSE: Endovascular therapy in addition to standard care (EVT+SC) has been demonstrated to be more effective than SC in acute ischemic large vessel occlusion stroke. Our aim was to determine the cost-effectiveness of EVT+SC depending on patients' initial National Institutes of Health Stroke Scale (NIHSS) score, time from symptom onset, Alberta Stroke Program Early CT Score (ASPECTS), and occlusion location. METHODS: A decision model based on Markov simulations estimated lifetime costs and quality-adjusted life years (QALYs) associated with both strategies applied in a US setting...
October 6, 2016: Stroke; a Journal of Cerebral Circulation
Iris K Minichmayr, André Schaeftlein, Joseph L Kuti, Markus Zeitlinger, Charlotte Kloft
OBJECTIVES: We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients. METHODS: Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid...
October 17, 2016: Clinical Pharmacokinetics
Luka Verrest, Thomas P C Dorlo
INTRODUCTION: Neglected tropical diseases (NTDs) affect more than one billion people, mainly living in developing countries. For most of these NTDs, treatment is suboptimal. To optimize treatment regimens, clinical pharmacokinetic studies are required where they have not been previously conducted to enable the use of pharmacometric modeling and simulation techniques in their application, which can provide substantial advantages. OBJECTIVES: Our aim was to provide a systematic overview and summary of all clinical pharmacokinetic studies in NTDs and to assess the use of pharmacometrics in these studies, as well as to identify which of the NTDs or which treatments have not been sufficiently studied...
October 15, 2016: Clinical Pharmacokinetics
Brett K Beaulieu-Jones, Casey S Greene
Patient interactions with health care providers result in entries to electronic health records (EHRs). EHRs were built for clinical and billing purposes but contain many data points about an individual. Mining these records provides opportunities to extract electronic phenotypes, which can be paired with genetic data to identify genes underlying common human diseases. This task remains challenging: high quality phenotyping is costly and requires physician review; many fields in the records are sparsely filled; and our definitions of diseases are continuing to improve over time...
October 12, 2016: Journal of Biomedical Informatics
Daniel H Li, James B Whitmore, Wentian Guo, Yuan Ji
Recent trials of adoptive cell therapy (ACT), such as the chimeric antigen receptor T (CAR-T) cells therapy, have demonstrated promising therapeutic effects for cancer patients. A main issue in the product development is to decide appropriate dose of ACT. Traditional phase 1 trial designs for cytotoxic agents explicitly assume that toxicity increases monotonically with dose levels and implicitly assume the same for efficacy to justify dose escalation. ACT usually induces rapid responses, and the monotonic dose-response assumption is unlikely to hold due to its immunobiological activities...
October 14, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Shashikant Srivastava, Devyani Deshpande, Jotam G Pasipanodya, Tania Thomas, Soumya Swaminathan, Eric Nuermberger, Tawanda Gumbo
Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Lauren Henke, Rojano Kashani, Deshan Yang, Tianyu Zhao, Olga Green, Lindsey Olsen, Vivian Rodriguez, H Omar Wooten, H Harold Li, Yanle Hu, Jeffrey Bradley, Clifford Robinson, Parag Parikh, Jeff Michalski, Sasa Mutic, Jeffrey R Olsen
PURPOSE: To characterize potential advantages of online-adaptive magnetic resonance (MR)-guided stereotactic body radiation therapy (SBRT) to treat oligometastatic disease of the non-liver abdomen and central thorax. METHODS AND MATERIALS: Ten patients treated with RT for unresectable primary or oligometastatic disease of the non-liver abdomen (n=5) or central thorax (n=5) underwent imaging throughout treatment on a clinical MR image guided RT system. The SBRT plans were created on the basis of tumor/organ at risk (OAR) anatomy at initial computed tomography simulation (PI), and simulated adaptive plans were created on the basis of observed MR image set tumor/OAR "anatomy of the day" (PA)...
August 31, 2016: International Journal of Radiation Oncology, Biology, Physics
A Lourenço, N Wellock, R Thomas, M Homer, H Bouchard, T Kanai, N MacDougall, G Royle, H Palmans
Water-equivalent plastics are frequently used in dosimetry for experimental simplicity. This work evaluates the water-equivalence of novel water-equivalent plastics specifically designed for light-ion beams, as well as commercially available plastics in a clinical high-energy carbon-ion beam. A plastic- to-water conversion factor [Formula: see text] was established to derive absorbed dose to water in a water phantom from ionization chamber readings performed in a plastic phantom. Three trial plastic materials with varying atomic compositions were produced and experimentally characterized in a high-energy carbon-ion beam...
October 14, 2016: Physics in Medicine and Biology
Michael Welter, Heiko Rieger
Tumor vasculature, the blood vessel network supplying a growing tumor with nutrients such as oxygen or glucose, is in many respects different from the hierarchically organized arterio-venous blood vessel network in normal tissues. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature. Integrative models, based on detailed experimental data and physical laws, implement, in silico, the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature...
2016: Advances in Experimental Medicine and Biology
Helena Edlund, Casper Steenholdt, Mark A Ainsworth, Eva Goebgen, Jørn Brynskov, Ole Ø Thomsen, Wilhelm Huisinga, Charlotte Kloft
Antibodies (Abs) against infliximab (IFX) increase IFX clearance and can result in treatment failure and acute hypersensitivity reactions. However, interpretation of their clinical value is complicated by individual differences in Ab responses and methods used for quantification. The increase in IFX clearance imposed by anti-IFX Abs has generally been evaluated using a binary classification, i.e., positive or negative. This analysis aimed to investigate if anti-IFX Ab concentrations provide a more adequate prediction of alterations in clearance...
October 13, 2016: AAPS Journal
A Mercuri, S Wu, S Stranzinger, S Mohr, S Salar-Behzadi, M Bresciani, E Fröhlich
This work aims to better understand the in vivo behaviour of modified release (MR) formulations (Envarsus(®) tablets and Advagraf(®) capsules) using in vitro properties of tacrolimus and in silico simulations. The in silico concentration profiles of tacrolimus released from the MR formulations were predicted after building a three compartments PK model with GastroPlus™, and using the experimentally determined in vitro physico-chemical properties as input parameters. In vitro-in vivo correlations (IVIVC) were obtained after deconvolution of in vivo data from a clinical trial...
October 10, 2016: International Journal of Pharmaceutics
Maartje S Jacobs, Femke Kaasenbrood, Maarten J Postma, Marinus van Hulst, Robert G Tieleman
AIMS: Atrial fibrillation (AF) is the most common arrhythmia and prevalence increases with age. Patients with AF have a high risk of stroke, and screening for AF is recommended in all people aged 65 years or older to identify patients eligible for stroke prevention. A handheld, single-lead electrocardiogram (ECG) device can be used for systematic screening in the population at risk. The objective of this study is to estimate the cost-effectiveness of screening for AF in primary care with the MyDiagnostick(®) during seasonal influenza vaccination in the Netherlands...
October 12, 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
Leonardo Petruzzi, Maria Rosaria Corbo, Milena Sinigaglia, Antonio Bevilacqua
Yeasts can remove ochratoxin A (OTA) in foods; however, we do not know if they can experience this ability in the gut. Thus, the aim of this paper was to study OTA binding by 3 wine strains of Saccharomyces cerevisiae (W13, W28, and the commercial isolate BM45) and S. cerevisiae var. boulardii ATCC MYA-796 (a probiotic yeast) after exposure to conditions simulating the passage through human gastrointestinal tract. Yeasts removed OTA by up to 44%, with a better ability found after gastrointestinal and sequential assays...
October 12, 2016: Journal of Food Science
Vaidotas Stankevicius, Gintautas Vasauskas, Danute Bulotiene, Stase Butkyte, Sonata Jarmalaite, Ricardas Rotomskis, Kestutis Suziedelis
BACKGROUND: The extracellular matrix (ECM), one of the key components of tumor microenvironment, has a tremendous impact on cancer development and highly influences tumor cell features. ECM affects vital cellular functions such as cell differentiation, migration, survival and proliferation. Gene and protein expression levels are regulated in cell-ECM interaction dependent manner as well. The rate of unsuccessful clinical trials, based on cell culture research models lacking the ECM microenvironment, indicates the need for alternative models and determines the shift to three-dimensional (3D) laminin rich ECM models, better simulating tissue organization...
October 11, 2016: BMC Cancer
Ying Zheng, Feng Pan, Sonja Sorensen
As the number of interventions available in a therapeutic area increases, the relevant decision questions in health technology assessment (HTA) expand to compare treatment sequences instead of discrete treatments and identify optimal sequences or position for a particular treatment in a sequence. The objective of this work was to review approaches used to model treatment sequences and provide practical guidance on conceptualizing whether and how to model sequences in health economic models. Economic models including treatment sequencing assessed by the National Institute for Health and Care Excellence were reviewed, as these assessments generally provide both policy relevance and comprehensive model detail...
October 8, 2016: PharmacoEconomics
Jinhyun Choi, Yong Bae Kim, Kyung Hwan Shin, Sung-Ja Ahn, Hyung-Sik Lee, Won Park, Su Ssan Kim, Jin Hee Kim, Kyu Chan Lee, Dong Won Kim, Hyun Suk Suh, Kyung Ran Park, Hyun Soo Shin, Chang-Ok Suh
PURPOSE: The aim of this study is to present the incidence of radiation pneumonitis (RP) reported within 6 months after treatment for breast cancer with or without internal mammary node irradiation (IMNI). METHODS: In the Korean Radiation Oncology Group (KROG) 08-06 phase III randomized trial, patients who were node-positive after surgery were randomly assigned to receive radiotherapy either with or without IMNI. A total of 747 patients were enrolled, and three-dimensional treatment planning with computed tomography simulation was performed for all patients...
September 2016: Journal of Breast Cancer
Martine Hoogendoorn, Talitha L Feenstra, Yumi Asukai, Andrew H Briggs, Sixten Borg, Roberto W Dal Negro, Ryan N Hansen, Sven-Arne Jansson, Reiner Leidl, Nancy Risebrough, Yevgeniy Samyshkin, Margarethe E Wacker, Maureen P M H Rutten-van Mölken
OBJECTIVES: To assess how suitable current chronic obstructive pulmonary disease (COPD) cost-effectiveness models are to evaluate personalized treatment options for COPD by exploring the type of heterogeneity included in current models and by validating outcomes for subgroups of patients. METHODS: A consortium of COPD modeling groups completed three tasks. First, they reported all patient characteristics included in the model and provided the level of detail in which the input parameters were specified...
September 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
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