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Clinical trial simulation

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https://www.readbyqxmd.com/read/28549780/patient-specific-pointer-tool-for-corrective-osteotomy-quality-of-symmetry-based-planning-and-case-study-of-ulnar-reconstruction-surgery
#1
Samuel Mueller, Lueder A Kahrs, Johannes Gaa, Tobias Ortmaier, Jan-Dierk Clausen, Christian Krettek
Malunion after forearm fractures are described to appear in 2% to 10% of cases. Reconstructive surgeries ensure adequate anatomical repositioning. Their importance derives from the fact that malunion can often lead to severe pain as well as deformities causing loss of function and aesthetic issues not only in the forearm, but also the wrist and elbow joint. In this paper a clinical case will be presented using a Patient Specific Instrument (PSI) as navigational aid for reconstructive surgery after malunion of a proximal ulnar fracture combined with allograft surgery of the radial head and radial condyle due to chronic traumatic radial head luxation (Monteggia fracture)...
May 11, 2017: Injury
https://www.readbyqxmd.com/read/28546227/keyboard-a-novel-bayesian-toxicity-probability-interval-design-for-phase-i-clinical-trials
#2
Fangrong Yan, Sumithra J Mandrekar, Ying Yuan
The primary objective of phase I oncology trials is to find the maximum tolerated dose (MTD). The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval...
May 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28545934/cure-modeling-in-real-time-prediction-how-much-does-it-help
#3
Gui-Shuang Ying, Qiang Zhang, Yu Lan, Yimei Li, Daniel F Heitjan
Various parametric and nonparametric modeling approaches exist for real-time prediction in time-to-event clinical trials. Recently, Chen (2016 BMC Biomedical Research Methodology 16) proposed a prediction method based on parametric cure-mixture modeling, intending to cover those situations where it appears that a non-negligible fraction of subjects is cured. In this article we apply a Weibull cure-mixture model to create predictions, demonstrating the approach in RTOG 0129, a randomized trial in head-and-neck cancer...
May 22, 2017: Contemporary Clinical Trials
https://www.readbyqxmd.com/read/28544854/algorithms-for-imputing-partially-observed-recurrent-events-with-applications-to-multiple-imputation-in-pattern-mixture-models
#4
Yongqiang Tang
Five algorithms are described for imputing partially observed recurrent events modeled by a negative binomial process, or more generally by a mixed Poisson process when the mean function for the recurrent events is continuous over time. We also discuss how to perform the imputation when the mean function of the event process has jump discontinuities. The validity of these algorithms is assessed by simulations. These imputation algorithms are potentially very useful in the implementation of pattern mixture models, which have been popularly used as sensitivity analysis under the non-ignorability assumption in clinical trials...
May 25, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28544622/an-investigation-into-the-two-stage-meta-analytic-copula-modelling-approach-for-evaluating-time-to-event-surrogate-endpoints-which-comprise-of-one-or-more-events-of-interest
#5
Natalie Dimier, Susan Todd
Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter-term surrogate endpoints as substitutes for costly long-term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long-term endpoint...
May 19, 2017: Pharmaceutical Statistics
https://www.readbyqxmd.com/read/28543940/greater-gains-in-spine-and-hip-strength-for-romosozumab-compared-to-teriparatide-in-postmenopausal-women-with-low-bone-mass
#6
T M Keaveny, D B Crittenden, M A Bolognese, H K Genant, K Engelke, B Oliveri, J P Brown, B L Langdahl, C Yan, A Grauer, C Libanati
Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a Phase II, randomized, placebo-controlled clinical trial of treatment-naïve postmenopausal women with low bone mass, romosozumab increased BMD at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis...
May 25, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28543626/smooth-semi-nonparametric-snp-estimation-of-the-cumulative-incidence-function
#7
Anh Nguyen Duc, Marcel Wolbers
This paper presents a novel approach to estimation of the cumulative incidence function in the presence of competing risks. The underlying statistical model is specified via a mixture factorization of the joint distribution of the event type and the time to the event. The time to event distributions conditional on the event type are modeled using smooth semi-nonparametric densities. One strength of this approach is that it can handle arbitrary censoring and truncation while relying on mild parametric assumptions...
May 23, 2017: Statistics in Medicine
https://www.readbyqxmd.com/read/28541602/three-dimensional-printing-in-cardiology-current-applications-and-future-challenges
#8
Hongxing Luo, Jarosław Meyer-Szary, Zhongmin Wang, Robert Sabiniewicz, Yuhao Liu
Three-dimensional (3D) printing has attracted a huge interest in recent years. Broadly speaking, it refers to the technology which converts a predesigned virtual model to a touchable object. In clinical medicine, it usually converts a series of two-dimensional medical images acquired through computed tomography, magnetic resonance imaging or 3D echocardiography into a physical model. Medical 3D printing consists of three main steps: image acquisition, virtual reconstruction and 3D manufacturing. It is a promising tool for preoperative evaluation, medical device design, hemodynamic simulation and medical education, it is also likely to reduce operative risk and increase operative success...
May 25, 2017: Cardiology Journal
https://www.readbyqxmd.com/read/28540639/exploiting-pharmacokinetic-models-of-tamoxifen-and-endoxifen-to-identify-factors-causing-subtherapeutic-concentrations-in-breast-cancer-patients
#9
Lena Klopp-Schulze, Markus Joerger, Sebastian G Wicha, Rob Ter Heine, Chantal Csajka, Zinnia P Parra-Guillen, Charlotte Kloft
BACKGROUND AND OBJECTIVES: A better understanding of the highly variable pharmacokinetics (PK) of tamoxifen and its active metabolite endoxifen in breast cancer patients is crucial to support individualised treatment. This study used a modelling and simulation approach to quantitatively assess the influence of cytochrome P450 (CYP) 2D6 activity and other relevant factors on tamoxifen and endoxifen PK to identify subgroups at risk for subtherapeutic endoxifen concentrations. METHODS: Simulations were performed using two previously published PK models jointly describing tamoxifen and endoxifen with CYP2D6 and CYP3A4/5 enzyme activities implemented as covariates...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28540638/in-silico-dose-prediction-for-long-acting-rilpivirine-and-cabotegravir-administration-to-children-and-adolescents
#10
Rajith K R Rajoli, David J Back, Steve Rannard, Caren Freel Meyers, Charles Flexner, Andrew Owen, Marco Siccardi
BACKGROUND AND OBJECTIVES: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28539069/real-world-challenges-for-hepatitis-c-virus-medications-a-critical-overview
#11
Imran Shahid, Waleed Hassan AlMalki, Sajida Hassan, Muhammad Hassan Hafeez
From 2010, the landscape of hepatitis C therapeutics has been changed rapidly, and today we are standing at a cusp of a pharmacological revolution where highly effective and interferon (IFN)-free direct acting antivirals (DAAs) are already on the market. Such treatment paradigms attain 90-95% sustained virologic response (SVR; undetectable viral load at week 12 or 24 at the end of therapy) rates in treated individuals compared to 50-70% with treatment completion of dual-therapy-pegylated interferon (PEG-IFN) and ribavirin (RBV)...
May 25, 2017: Critical Reviews in Microbiology
https://www.readbyqxmd.com/read/28538639/development-of-the-emergency-preservation-and-resuscitation-for-cardiac-arrest-from-trauma-epr-cat-clinical-trial
#12
Samuel A Tisherman, Hasan B Alam, Peter M Rhee, Thomas M Scalea, Tomas Drabek, Raquel M Forsythe, Patrick M Kochanek McCm
BACKGROUND: Patients who suffer a cardiac arrest from trauma rarely survive, even with aggressive resuscitation attempts, including an Emergency Department (ED) thoracotomy. Emergency Preservation and Resuscitation (EPR) was developed to utilize hypothermia to buy time to obtain hemostasis before irreversible organ damage occurs. Large animal studies have demonstrated that cooling to tympanic membrane temperature 10°C during exsanguination cardiac arrest can allow up to 2 hours of circulatory arrest and repair of simulated injuries with normal neurologic recovery...
May 22, 2017: Journal of Trauma and Acute Care Surgery
https://www.readbyqxmd.com/read/28536774/physiologically-based-pharmacokinetic-modelling-and-prediction-of-metformin-pharmacokinetics-in-renal-hepatic-impaired-young-adults-and-elderly-populations
#13
Su-Jin Rhee, Hyewon Chung, SoJeong Yi, Kyung-Sang Yu, Jae-Yong Chung
BACKGROUND AND OBJECTIVES: Physiologically based pharmacokinetic (PBPK) modelling and simulation enable researchers to overcome practical limitations for clinical trials on special populations. This study was conducted to investigate how the PBPK model describes the pharmacokinetics of metformin in young adult and elderly populations and to predict the pharmacokinetics of metformin in patients with renal or hepatic impairment in both populations. METHODS: A first-order absorption/PBPK model for metformin was built in the Simcyp simulator version 14 release 1...
May 23, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28535410/effect-of-enzyme-inhibition-on-perampanel-pharmacokinetics-why-study-design-matters
#14
Barry E Gidal, Rama Maganti, Antonio Laurenza, Haichen Yang, David A Verbel, Edgar Schuck, Jim Ferry
OBJECTIVES: Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions-enzyme inhibition or induction-and anticipating their occurrence are important for management of patients with epilepsy...
April 26, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28532387/robust-estimation-of-the-expected-survival-probabilities-from-high-dimensional-cox-models-with-biomarker-by-treatment-interactions-in-randomized-clinical-trials
#15
Nils Ternès, Federico Rotolo, Stefan Michiels
BACKGROUND: Thanks to the advances in genomics and targeted treatments, more and more prediction models based on biomarkers are being developed to predict potential benefit from treatments in a randomized clinical trial. Despite the methodological framework for the development and validation of prediction models in a high-dimensional setting is getting more and more established, no clear guidance exists yet on how to estimate expected survival probabilities in a penalized model with biomarker-by-treatment interactions...
May 22, 2017: BMC Medical Research Methodology
https://www.readbyqxmd.com/read/28531203/potential-health-gains-for-patients-with-metastatic-renal-cell-carcinoma-in-daily-clinical-practice-a-real-world-cost-effectiveness-analysis-of-sequential-first-and-second-line-treatments
#16
S De Groot, H M Blommestein, W K Redekop, S Sleijfer, L A L M Kiemeney, E Oosterwijk, C A Uyl-de Groot
INTRODUCTION: Randomised controlled trials have shown that targeted therapies like sunitinib are effective in metastatic renal cell carcinoma (mRCC). Little is known about the current use of these therapies, and their associated costs and effects in daily clinical practice. We estimated the real-world cost-effectiveness of different treatment strategies comprising one or more sequentially administered drugs. METHODS: Analyses were performed using patient-level data from a Dutch population-based registry including patients diagnosed with primary mRCC from January 2008 to December 2010 (i...
2017: PloS One
https://www.readbyqxmd.com/read/28530853/designing-clinical-trials-that-accept-new-arms-an-example-in-metastatic-breast-cancer
#17
Steffen Ventz, Brian M Alexander, Giovanni Parmigiani, Richard D Gelber, Lorenzo Trippa
Purpose The majority of randomized oncology trials are two-arm studies that test the efficacy of new therapies against a standard of care, thereby assigning a large proportion of patients to nonexperimental therapies. In contrast, multiarm studies efficiently share a common control arm while evaluating multiple experimental therapies. A major bottleneck for traditional multiarm trials is the requirement that all therapies-often drugs from different companies-have to be available at the same time when the trial starts...
May 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28530492/3d-printing-in-liver-surgery-a-systematic-review
#18
Jan Sylwester Witowski, Jasamine Coles-Black, Tomasz Zbigniew Zuzak, Michał Pędziwiatr, Jason Chuen, Piotr Major, Andrzej Budzyński
BACKGROUND: Rapid growth of three-dimensional (3D) printing in recent years has led to new applications of this technology across all medical fields. This review article presents a broad range of examples on how 3D printing is facilitating liver surgery, including models for preoperative planning, education, and simulation. MATERIALS AND METHODS: We have performed an extensive search of the medical databases Ovid/MEDLINE and PubMed/EMBASE and screened articles fitting the scope of review, following previously established exclusion criteria...
May 22, 2017: Telemedicine Journal and E-health: the Official Journal of the American Telemedicine Association
https://www.readbyqxmd.com/read/28528578/a-cluster-randomized-trial-to-reduce-caesarean-delivery-rates-in-quebec-cost-effectiveness-analysis
#19
Mira Johri, Edmond S W Ng, Clara Bermudez-Tamayo, Jeffrey S Hoch, Thierry Ducruet, Nils Chaillet
BACKGROUND: Widespread increases in caesarean section (CS) rates have sparked concerns about risks to mothers and infants and rising healthcare costs. A multicentre, two-arm, cluster-randomized trial in Quebec, Canada assessed whether an audit and feedback intervention targeting health professionals would reduce CS rates for pregnant women compared to usual care, and concluded that it reduced CS rates without adverse effects on maternal or neonatal health. The effect was statistically significant but clinically small...
May 22, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28522422/statistical-design-for-a-confirmatory-trial-with-a-continuous-predictive-biomarker-a-case-study
#20
Adarsh Joshi, Jenny Zhang, Liang Fang
With targeted therapies, it is often hypothesized that their effect may be specific to the subpopulation in which the target pathway is activated. We consider the problem of designing a confirmatory trial when the biological hypothesis of the experimental therapy is strongly supported by the pre-clinical data but limited clinical data is available to pre-define a subpopulation based on a biomarker with continuous values. The study design is further complicated if interim evaluations of the biomarker-based subpopulations are also being considered...
May 15, 2017: Contemporary Clinical Trials
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