Form follows function:model-driven engineering for clinical trials

We argue that, for certain constrained domains, elaborate model transformation technologies-implemented from scratch in general-purpose programming languages-are unnecessary for model-driven engineering; instead, lightweight configuration of commercial off-the-shelf productivity tools suffices. In particular, in the CancerGrid project, we have been developing model-driven techniques for the generation of software tools to support clinical trials. A domain metamodel captures the community's best practice in trial design. A scientist authors a trial protocol, modelling their trial by instantiating the metamodel; customized software artifacts to support trial execution are generated automatically from the scientist's model. The metamodel is expressed as an XML Schema, in such a way that it can be instantiated by completing a form to generate a conformant XML document. The same process works at a second level for trial execution: among the artifacts generated from the protocol are models of the data to be collected, and the clinician conducting the trial instantiates such models in reporting observations-again by completing a form to create a conformant XML document, representing the data gathered during that observation. Simple standard form management tools are all that is needed. Our approach is applicable to a wide variety of information-modelling domains: not just clinical trials, but also electronic public sector computing, customer relationship management, document workflow, and so on. © 2012 Springer-Verlag.

Children's views on unlicensed/off-label paediatric prescribing and paediatric clinical trials

Objectives - To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. Methods - Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. Results - A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. Conclusions - This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. Practice implications - Health care professionals should consider the views of children in decisions that affect their health.

Healthcare professional experiences and attitudes on unlicensed/off-label paediatric prescribing and paediatric clinical trials

To investigate the knowledge and views of a range of healthcare professionals (consultant paediatricians, general practitioners (GPs), community pharmacists and paediatric nurses) regarding the use of unlicensed/off-label medicines in children and the participation of children in clinical trials.

Age-related macular degeneration and nutritional supplementation:a review of randomised controlled trials

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in the developed world. The lack of effective treatment modalities, coupled with evidence supporting an oxidative pathogenesis, has increased interest in the potential preventative role of nutritional supplementation. This article reviews seven randomised controlled trials (RCTs) that have investigated the role of nutritional supplementation in AMD. Three of these trials reported a positive effect of nutritional supplementation on AMD; the Age-related eye study (AREDS), the Lutein Antioxidant Supplementation Trial (LAST), and the oral zinc trial by Newsome et al. (1988). However, the oral zinc trial by Newsome et al. (1988) was unlikely to detect any difference between treatments smaller than 72%, and the AREDS results were based on a subgroup of their study population. Lutein was considered for the AREDS formulation, but was not commercially available at that time. The findings of the LAST support a possible therapeutic role of lutein in AMD. © 2004 The College of Optometrists.

Pronounced reduction of postprandial glucagon by lixisenatide:a meta-analysis of randomized clinical trials

Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. Methods: Six randomized, placebo-controlled studies of lixisenatide 20μg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. Results: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9mmol/l, p<0.001) and glucose excursion (LS mean difference vs. placebo: -4.5mmol/l, p<0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0ng/l, p<0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p<0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. Conclusions: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion. © 2014 John Wiley and Sons Ltd.

Systematic review investigating the reporting of comorbidities and medication in randomized controlled trials of people with dementia

Objectives: dementia is a debilitating condition characterised by global loss of cognitive and intellectual functioning, which reduces social and occupational performance. This population frequently presents with medical co-morbidities such as hypertension, cardiovascular disease and diabetes. The CONSORT statement outlines recommended guidance on reporting of participant characteristics in clinical trials. It is, however, unclear how much these are adhered to in trials assessing people with dementia. This paper assesses the reporting of medical co-morbidities and prescribed medications for people with dementia within randomised controlled trial (RCT) reports. Design: a systematic review of the published literature from the databases AMED, CINAHL, MEDLINE, EMBASE and the Cochrane Clinical Trial Registry from 1 January 1997 to 9 January 2014 was undertaken in order to identify RCTs detailing baseline medical co-morbidities and prescribed medications . Eligible studies were appraised using the Critical Appraisal Skills Programme (CASP) RCT appraisal tool, and descriptive statistical analyses were calculated to determine point prevalence. Results: nine trials, including 1474 people with dementia, were identified presenting medical co-morbidity data. These indicated neurological disorders ( prevalence 91%), vascular disorders (prevalence 91%), cardiac disorders ( prevalence 74%) and ischaemic cerebrovascular disease ( prevalence 53%) were most frequently seen. Conclusions: published RCTs poorly report medical co-morbidities and medications for people with dementia. Future trials should include the report of these items to allow interpretation of whether the results are generalisable to frailer older populations.

Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes

Aims : Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. Methods : We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. Results : Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. Conclusions : Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

The role of death qualification in venirepersons' evaluations of aggravating and mitigating circumstances in capital trials

Death qualification is a part of voir dire that is unique to capital trials. Unlike all other litigation, capital jurors must affirm their willingness to impose both legal standards (either life in prison or the death penalty). Jurors who assert they are able to do so are deemed “death-qualified” and are eligible for capital jury service: jurors who assert that they are unable to do so are deemed “excludable” or “scrupled” and are barred from hearing a death penalty case. During the penalty phase in capital trials, death-qualified jurors weigh the aggravators (i.e., arguments for death) against the mitigators (i.e., arguments for life) in order to determine the sentence. If the aggravating circumstances outweigh the mitigating circumstances, then the jury is to recommend death; if the mitigating circumstances outweigh the aggravating circumstances, then the jury is to recommend life. The jury is free to weigh each aggravating and mitigating circumstance in any matter they see fit. Previous research has found that death qualification impacts jurors' receptiveness to aggravating and mitigating circumstances (e.g., Luginbuhl & Middendorf, 1988). However, these studies utilized the now-defunct Witherspoon rule and did not include a case scenario for participants to reference. The purpose of this study was to investigate whether death qualification affects jurors' endorsements of aggravating and mitigating circumstances when Witt, rather than Witherspoon, is the legal standard for death qualification. Four hundred and fifty venirepersons from the 11 th Judicial Circuit in Miami, Florida completed a booklet of stimulus materials that contained the following: two death qualification questions; a case scenario that included a summary of the guilt and penalty phases of a capital case; a 26-item measure that required participants to endorse aggravators, nonstatutory mitigators, and statutory mitigators on a 6-point Likert scale; and standard demographic questions. Results indicated that death-qualified venirepersons, when compared to excludables, were more likely to endorse aggravating circumstances. Excludable participants, when compared to death-qualified venirepersons, were more likely to endorse nonstatutory mitigators. There was no significant difference between death-qualified and excludable venirepersons with respect to their endorsement of 6 out of 7 statutory mitigators. It would appear that the Furman v. Georgia (1972) decision to declare the death penalty unconstitutional is frustrated by the Lockhart v. McCree (1986) affirmation of death qualification. ^

Methods and processes for development of a CONSORT extension for reporting pilot randomized controlled trials

Peer reviewed

Should weight loss and maintenance programmes be designed differently for men? : A systematic review of long-term randomised controlled trials presenting data for men and women: The ROMEO project

Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved. Acknowledgements This review is one of a series of systematic reviews for the ROMEO project (Review Of MEn and Obesity), funded by the National Institute for Health Research, Health Technology Assessment Programme (NIHR HTA Project 09/127/01; Systematic reviews and integrated report on the quantitative and qualitative evidence base for the management of obesity in men http://www.hta.ac.uk/2545). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. HERU, HSRU and NMAHP are funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The authors accept full responsibility for this publication. We would also like to thank the Men's Health Forums of Scotland, Ireland, England and Wales: Tim Street, Paula Carroll, Colin Fowler and David Wilkins. We also thank Kate Jolly for further information about the Lighten Up trial.

Should weight loss and maintenance programmes be designed differently for men? : A systematic review of long-term randomised controlled trials presenting data for men and women: The ROMEO project

Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved. Acknowledgements This review is one of a series of systematic reviews for the ROMEO project (Review Of MEn and Obesity), funded by the National Institute for Health Research, Health Technology Assessment Programme (NIHR HTA Project 09/127/01; Systematic reviews and integrated report on the quantitative and qualitative evidence base for the management of obesity in men http://www.hta.ac.uk/2545). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. HERU, HSRU and NMAHP are funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The authors accept full responsibility for this publication. We would also like to thank the Men's Health Forums of Scotland, Ireland, England and Wales: Tim Street, Paula Carroll, Colin Fowler and David Wilkins. We also thank Kate Jolly for further information about the Lighten Up trial.

Task-switch costs subsequent to cue-only trials

Acknowledgements The authors would like to thank Fiona Carr, Carmen Horne, and Brigitta Toth for assistance with data collection. Disclosure statement No potential conflict of interest was reported by the authors. Funding information The authors would like to thank the School of Psychology, University of Aberdeen, for contributing funding for participant payments.

Decision aids for people considering taking part in clinical trials

Peer reviewed

A protocol for a systematic review of non-randomised evaluations of strategies to improve participant recruitment to randomised controlled trials

Peer reviewed