Failure to report protocol violations in clinical trials: a threat to internal validity?

<p>Abstract</p> <p>Background</p> <p>Excessive protocol violations (PV), which can be defined as preventable mistakes in study conduct, may result in patient harm and introduce errors into a clinical trial's results leading to flawed trial conclusions.</p> <p>The purpose of this project was to gain a better understanding of reported PVs, to describe current practice with regards to the use of methods for the reduction of PVs and to investigate relationships between clinical trial characteristics and PVs.</p> <p>Methods</p> <p>We reviewed 80 clinical trials conducted across a broad range of medical specialties published in four major general medical journals (The Lancet, NEJM, JAMA, BMJ). Eligible papers were identified using a PubMed search. For each included trial, two authors independently abstracted information on trial characteristics, PV reporting and PV rates and interventions used to reduce PVs. PVs were categorised into one of five distinct types: enrolment, randomisation, study intervention, patient compliance and data collection errors. Associations between PVs and study characteristics were investigated using logistic regression.</p> <p>Results</p> <p>Eighty clinical trials (20 from each journal) were identified from 101 consecutive PubMed abstracts. The median number of participants was 701 (range: 20 to 162, 367) and the median number of participating sites was 15 (range: 1 to 701). Nineteen percent (15/80) of included trials were single centre trials. The median study duration was 24 months (range: 5.81 - 127 months) and 74% (59/80) of included trials were primarily academic funded.</p> <p>Thirty two percent (26/80) of included trials failed to provide explicit reporting of any type of PV and none (0/80) of the trials provided explicit reporting of all five types of PVs. Larger clinical trials (more patients, more sites, longer duration, more complex management structure) were more likely to have more complete reporting of PV's.</p> <p>Only 9% (7/80) of trials reported the use of a specific study method to prevent PVs. Use of a run-in phase was the only method reported.</p> <p>Conclusions</p> <p>PVs are under-reported. Although the CONSORT statement provides guidance on the reporting of PVs, reporting requirements are not explicit for all types of PVs. As a first step towards improved reporting by authors, we recommend the CONSORT statement highlight the importance of PVs by making reporting requirements more explicit.</p

A systematic review of techniques and interventions for improving adherence to inclusion and exclusion criteria during enrolment into randomised controlled trials

<p>Abstract</p> <p>Background</p> <p>Enrolment of patients into a randomised controlled trial (RCT) in violation of key inclusion or exclusion criteria, may lead to excess avoidable harm. The purpose of this paper was to systematically identify and review techniques and interventions proven to prevent or avoid inappropriate enrolment of patients into RCTs.</p> <p>Methods</p> <p>EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, online abstract repositories, and conference websites were searched. Experts were contacted and bibliographies of retrieved papers hand-searched. The search cut-off date was 31 August 2009.</p> <p>Results</p> <p>No primary publications were found. We identified one study in the grey literature (conference abstracts and presentations) reporting the results of an evaluation of the effectiveness of an intervention designed to prevent or avoid inappropriate enrolment of patients into an RCT. In the context of a multicentre trial, use of a dummy enrolment run-in phase was shown to reduce enrolment errors significantly (<it>P </it>< 0.001), from 16.1% during the run-in phase to < 1% after trial initiation.</p> <p>Conclusions</p> <p>Our systematic search yielded only one technique or intervention shown to improve adherence to eligibility criteria during enrolment into RCTs. Given the potential harm involved in recruiting patients into a clinical trial in violation of key eligibility criteria, future research is needed to better inform those conducting clinical trials of how best to prevent enrolment errors</p

In vitro evaluation of sustained released matrix tablets containing ibuprofen: a model poorly water-soluble drug

ABSTRACT A matrix system was developed that releases ibuprofen (IB) over a 12-hour period and the influence of the polymer type and concentration on the release rate of the drug was evaluated. Tablets containing different concentrations of Carbopol (CP), hydroxypropyl methylcellulose (HPMC), or ethyl cellulose (EC) were prepared using direct compression and the drug content, content uniformity, hardness, friability, dissolution performance, and in vitro release kinetics were examined. Formulated tablets were found to be within acceptable limits for physical and chemical parameters. The release kinetics of the Carbopol(r)971P 8% formulation showed the best linearity (r 2 =0.977) in fitting zero-order kinetics, suggesting the release rate was time independent. The drug release from tablets containing 8% CP was extended over approximately 18 hours and the release kinetics were nearly linear, suggesting that this system has the potential to maintain constant plasma drug concentrations over 12 hours, which could reduce the frequency of administration and the occurrence of adverse effects associated with repeated administration of conventional IB tablets

Long Covid active case finding study protocol: A co-produced community-based pilot within the STIMULATE-ICP study (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways)

Background and aim Long Covid is a significant public health concern with potentially negative implications for health inequalities. We know that those who are already socially disadvantaged in society are more exposed to COVID-19, experience the worst health outcomes and are more likely to suffer economically. We also know that these groups are more likely to experience stigma and have negative healthcare experiences even before the pandemic. However, little is known about disadvantaged groups' experiences of Long Covid, and preliminary evidence suggests they may be under-represented in those who access formal care. We will conduct a pilot study in a defined geographical area in London, United Kingdom to test the feasibility of a community-based approach of identifying Long Covid cases that have not been clinically diagnosed and have not been referred to Long Covid specialist services. We will explore the barriers to accessing recognition, care, and support, as well as experiences of stigma and perceived discrimination. Methods This protocol and study materials were co-produced with a Community Advisory Board (CAB) made up primarily of people living with Long Covid. Working with voluntary organisations, a study leaflet will be distributed in the local community to highlight Long Covid symptoms and invite those experiencing them to participate in the study if they are not formally diagnosed. Potential participants will be assessed according to the study's inclusion criteria and offered the opportunity to participate if they fit them. Awareness of Long Covid and associated symptoms, experiences of trying to access care, as well as stigma and discrimination will be explored through qualitative interviews with participants. Upon completion of the interviews, participants will be offered a referral to the local social prescribing team to receive support that is personalised to them potentially including, but not restricted to, liaising with their primary care provider and the regional Long Covid clinic

Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial

Importance: Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness. Objective: To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients. Design, setting, and participants: Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2\ua0days. Interventions: Random allocation to receive a daily supplement of up to 100\ua0g of IV amino acids or standard care. Main outcomes and measures: Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin\ua0C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function. Results: 474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE\ua0II scores (20.2\ua0±\ua06.8 vs. 21.7\ua0±\ua07.6, P\ua0=\ua00.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P\ua0=\ua00.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21\ua0AKI days per 10\ua0patient ICU days, 95\ua0% CI −0.27 to 1.04, P\ua0=\ua00.45). Amino acid therapy significantly improved eGFR (treatment group\ua0×\ua0time interaction, P\ua0=\ua00.004), with an early peak difference of 7.7\ua0mL/min/1.73\ua0m (95\ua0% CI 1.0–14.5\ua0mL/min/1.73\ua0m, P\ua0=\ua00.02) on study day\ua04. Daily urine output was also significantly increased (+300\ua0mL/day, 95\ua0% CI 145–455\ua0mL, P\ua0=\ua00.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P\ua0=\ua00.062); however, this trend was not present after controlling for baseline imbalance (P\ua0=\ua00.21). Conclusion and relevance: Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction. Trial registration: anzctr.org.au Identifier: ACTRN12609001015235

Scouting for girls? Gender and the Scout Movement in Britain

This article was published in the journal, Gender, Place and Culture [© Taylor & Francis (Routledge)] and the definitive version is available at: http://dx.doi.org/10.1080/0966369X.2011.583342This article brings a feminist geopolitics to bear upon an analysis of the Boy Scout Movement in Britain in order to illustrate how an emphasis upon seemingly banal, embodied practices such as dressing, writing and crafting can provide a counter-view to prevailing notions of the elite, organisational `scripting' of individualised, geopolitical identities. Here, these practices undertaken by girls are understood not as subversive, or even transgressive, in the face of broader-scale constructions of the self and the collective body, but rather as related moments in the emergence of a complex, tension-ridden `movement' that exceed specific attempts at fixity along the lines of gender. Using archival data, this article examines various embodied practices by `girl scouts' that were made possible by such attempts at fixity but which also, in turn, opened up new spaces of engagement and negotiation. A cumulative shift from a determinedly masculine to a co-educational organisation over the course of the twentieth century thus reflects complex geographies of gender, national identity and citizenship and offers a historical contribution to the feminist geopolitics literature