ACGT: advancing clinico-genomic trials on cancer - four years of experience.

The challenges regarding seamless integration of distributed, heterogeneous and multilevel data arising in the context of contemporary, post-genomic clinical trials cannot be effectively addressed with current methodologies. An urgent need exists to access data in a uniform manner, to share information among different clinical and research centers, and to store data in secure repositories assuring the privacy of patients. Advancing Clinico-Genomic Trials (ACGT) was a European Commission funded Integrated Project that aimed at providing tools and methods to enhance the efficiency of clinical trials in the -omics era. The project, now completed after four years of work, involved the development of both a set of methodological approaches as well as tools and services and its testing in the context of real-world clinico-genomic scenarios. This paper describes the main experiences using the ACGT platform and its tools within one such scenario and highlights the very promising results obtained.

A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer's disease and Parkinson's disease

Acknowledgements This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124). The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report or for the decision to submit for publication.

Biologic therapies and non-melanoma skin cancer rates in three chronic immune-mediated diseases

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-I trials

Objectives: To investigate the effectiveness of valerian for the management of chronic insomnia in general practice. Design: Valerian versus placebo in a series of n-of-1 trials, in Queensland, Australia. Results: Of 42 enrolled patients, 24 (57%) had sufficient data for inclusion into the n-of-1 analysis. Response to valerian was fair for 23 (96%) participants evaluating their 'energy level in the previous day' but poor or modest for all 24 (100%) participants' response to 'total sleep time' and for 23 (96%) participants' response to 'number of night awakenings' and 'morning refreshment'. As a group, the proportion of treatment successes ranged from 0.35 (95% CI 0.23, 0.47) to 0.55 (95% CI 0.43, 0.67) for the six elicited outcome sleep variables. There was no significant difference in the number (P = 0.06), distribution (P = 1.00) or severity (P = 0.46) of side effects between valerian and placebo treatments. Conclusions: Valerian was not shown to be appreciably better than placebo in promoting sleep or sleep-related factors for any individual patient or for all patients as a group. (C) 2003 Elsevier Ltd. All rights reserved.

Using patients' and rheumatologists' opinions to specify a short form of the WOMAC function subscale

Background: The WOMAC ( Western Ontario and McMaster Universities) function subscale is widely used in clinical trials of hip and knee osteoarthritis. Reducing the number of items of the subscale would enhance efficiency and compliance, particularly for use in clinical practice applications. Objective: To develop a short form of the WOMAC function subscale based on patients' and experts' opinions ( WOMAC function short form). Methods: WOMAC function subscale data ( Likert version) were obtained from 1218 outpatients with painful hip or knee osteoarthritis. These patients and their rheumatologists selected the five items that they considered most in need of improvement. The rheumatologists were asked to select the five items for which patients in general are the most impaired. Items that were least important to patients and experts, those with a high proportion of missing data, and those with a response distribution showing a floor or ceiling response were excluded, along with one of a pair of items with a correlation coefficient >0.75. Results: The WOMAC function short form included items 1, 2, 3, 6, 7, 8, 9, and 15 of the long form. The short form did not differ substantially from the long form in responsiveness ( standardised response mean of 0.84 v 0.80). Conclusions: A short form of the WOMAC function subscale was developed according to the views of patients and rheumatologists, based on the responses of 1218 patients and 399 rheumatologists. The clinical relevance and applicability of this WOMAC function subscale short form require further evaluation.

Tumour necrosis factor inhibitors

The cytokine, tumour necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors (etanercept, infliximab and adalimumab) significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. For reasons that are not entirely clear, etanercept does not work in Crohn's disease. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis, are under evaluation in long-term follow-up studies. The TNF inhibitors are expensive (about $18000 per year), and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.

Who's really hypertensive? - Quality control issues in the assessment of blood pressure for randomized trials

The characterization of blood pressure in treatment trials assessing the benefits of blood pressure lowering regimens is a critical factor for the appropriate interpretation of study results. With numerous operators involved in the measurement of blood pressure in many thousands of patients being screened for entry into clinical trials, it is essential that operators follow pre-defined measurement protocols involving multiple measurements and standardized techniques. Blood pressure measurement protocols have been developed by international societies and emphasize the importance of appropriate choice of cuff size, identification of Korotkoff sounds, and digit preference. Training of operators and auditing of blood pressure measurement may assist in reducing the operator-related errors in measurement. This paper describes the quality control activities adopted for the screening stage of the 2nd Australian National Blood Pressure Study (ANBP2). ANBP2 is cardiovascular outcome trial of the treatment of hypertension in the elderly that was conducted entirely in general practices in Australia. A total of 54 288 subjects were screened; 3688 previously untreated subjects were identified as having blood pressure >140/90 mmHg at the initial screening visit, 898 (24%) were not eligible for study entry after two further visits due to the elevated reading not being sustained. For both systolic and diastolic blood pressure recording, observed digit preference fell within 7 percentage points of the expected frequency. Protocol adherence, in terms of the required minimum blood pressure difference between the last two successive recordings, was 99.8%. These data suggest that adherence to blood pressure recording protocols and elimination of digit preferences can be achieved through appropriate training programs and quality control activities in large multi-centre community-based trials in general practice. Repeated blood pressure measurement prior to initial diagnosis and study entry is essential to appropriately characterize hypertension in these elderly patients.

Appraising the quality of randomized controlled trials: inter-rater reliability for the OTseeker evidence database

Rationale and aims 'OTseeker' is an online database of randomized controlled trials (RCTs) and systematic reviews relevant to occupational therapy. RCTs are critically appraised and rated for quality using the 'PEDro' scale. We aimed to investigate the inter-rater reliability of the PEDro scale before and after revising rating guidelines. Methods In study 1, five raters scored 100 RCTs using the original PEDro scale guidelines. In study 2, two raters scored 40 different RCTs using revised guidelines. All RCTs were randomly selected from the OTseeker database. Reliability was calculated using Kappa and intraclass correlation coefficients [ICC (model 2,1)]. Results Inter-rater reliability was 'good to excellent' in the first study (Kappas >= 0.53; ICCs >= 0.71). After revising the rating guidelines, the reliability levels were equivalent or higher to those previously obtained (Kappas >= 0.53; ICCs >= 0.89), except for the item, 'groups similar at baseline', which still had moderate reliability (Kappa = 0.53). In study 2, two PEDro scale items, which had their definitions revised, 'less than 15% dropout' and 'point measures and variability', showed higher reliability. In both studies, the PEDro items with the lowest reliability were 'groups similar at baseline' (Kappas = 0.53), 'less than 15% dropout' (Kappas

A Comparison of Methodologies from Two Longitudinal Community-Based Randomized Controlled Trials of Similar Interventions in Palliative Care: What Worked and What Did Not

Background: Methodological challenges such as recruitment problems and participant burden make clinical trials in palliative care difficult. In 2001-2004, two community-based randomized controlled trials (RCTs) of case conferences in palliative care settings were independently conducted in Australia-the Queensland Case Conferences trial (QCC) and the Palliative Care Trial (PCT). Design: A structured comparative study of the QCC and PCT was conducted, organized by known practical and organizational barriers to clinical trials in palliative care. Results: Differences in funding dictated study designs and recruitment success; PCT had 6 times the budget of QCC. Sample size attainment. Only PCT achieved the sample size goal. QCC focused on reducing attrition through gatekeeping while PCT maximized participation through detailed recruitment strategies and planned for significant attrition. Testing sustainable interventions. QCC achieved a higher percentage of planned case conferences; the QCC strategy required minimal extra work for clinicians while PCT superimposed conferences on normal work schedules. Minimizing participant burden. Differing strategies of data collection were implemented to reduce participant burden. QCC had short survey instruments. PCT incorporated all data collection into normal clinical nursing encounters. Other. Both studies had acceptable withdrawal rates. Intention-to-treat analyses are planned. Both studies included substudies to validate new outcome measures. Conclusions: Health service interventions in palliative care can be studied using RCTs. Detailed comparative information of strategies, successes and challenges can inform the design of future trials. Key lessons include adequate funding, recruitment focus, sustainable interventions, and mechanisms to minimize participant burden.

Complement factor 5a as a therapeutic target

The complement system is an innate immune defense mechanism that protects the host from infection and injury. Complement activation results in the formation of anaphylatoxins, including the biologically active protein C5a. This anaphylatoxin is a potent chemotactic agent for immune and inflammatory cells and induces cell activation. In situations of excessive or uncontrolled complement activation, the overproduction of C5a can cause deleterious effects to the host, and this process is implicated in the pathogenesis of numerous immunoinflammatory disease states, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, ischemia-reperfusion injuries and others. The presence of C5a in a wide variety of condition's has prompted many groups to examine the potential of inhibiting this complement activation product, with the aim of controlling these diseases and reducing the pathologic process. However, to date there is no clinically available specific C5a inhibitor and development of this new drug class is still in a relatively early stage, although limited phase I and phase II human clinical trials have been undertaken in the last few years with selected agents. In this review, examination of the current evidence supporting a specific role of C5a in selected disease states and an overview of potential therapeutic C5a inhibitors will enable the critical evaluation of the potential for C5a as a therapeutic target.

Cautionary tales in the interpretation of systematic reviews of therapy trials

This is the second in a series of articles emphasizing the cautions in the interpretation of health-care studies. Systematic reviews are presented as comprehensive, unbiased summaries of evidence and are often referred to by clinicians, guideline developers and health policy-makers. Their strengths and limitations, and how their results can be subject to bias and misinterpretation, are discussed.

Inappropriate oral formulations and information in paediatric trials

Previously, quality of formulations information provided for oral medications used in paediatric clinical trials published in 10 highly cited journals between 2002 and 2004 raised concerns. This short report explores if there was any subsequent improvement on how the formulations used in trials involving children

Concise review:bone marrow for the treatment of spinal cord injury: mechanisms and clinical applications

Transplantation of bone marrow stem cells into spinal cord lesions enhances axonal regeneration and promotes functional recovery in animal studies. There are two types of adult bone marrow stem cell; hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). The mechanisms by which HSCs and MSCs might promote spinal cord repair following transplantation have been extensively investigated. The objective of this review is to discuss these mechanisms; we briefly consider the controversial topic of HSC and MSC transdifferentiation into central nervous system cells but focus on the neurotrophic, tissue sparing, and reparative action of MSC grafts in the context of the spinal cord injury (SCI) milieu. We then discuss some of the specific issues related to the translation of HSC and MSC therapies for patients with SCI and present a comprehensive critique of the current bone marrow cell clinical trials for the treatment of SCI to date.

WSRF-based modeling of clinical trial information for collaborative cancer research

The CancerGrid consortium is developing open-standards cancer informatics to address the challenges posed by modern cancer clinical trials. This paper presents the service-oriented software paradigm implemented in CancerGrid to derive clinical trial information management systems for collaborative cancer research across multiple institutions. Our proposal is founded on a combination of a clinical trial (meta)model and WSRF (Web Services Resource Framework), and is currently being evaluated for use in early phase trials. Although primarily targeted at cancer research, our approach is readily applicable to other areas for which a similar information model is available.

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.