Trials
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In recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials. ⋯ Adaptive designs are now well established in the drug development landscape. If properly pre-planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated.
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Most adult intensive care units (ICUs) worldwide adopt restrictive family visitation models (RFVMs). However, evidence, mostly from non-randomized studies, suggests that flexible adult ICU visiting hours are safe policies that can result in benefits such as prevention of delirium and increase in satisfaction with care. Accordingly, the ICU Visits Study was designed to compare the effectiveness and safety of a flexible family visitation model (FFVM) vs. an RFVM on delirium prevention among ICU patients, and also to analyze its potential effects on family members and ICU professionals. ⋯ This a priori statistical analysis plan aims to enhance the transparency of our study, facilitating unbiased analyses of ICU visit study data, and provide guidance for statistical analysis for groups conducting studies in the same field.
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Approximately 70,000 to 75,000 proximal femoral fracture repairs take place in the UK each year. Hemiarthroplasty is the preferred treatment for adults aged over 60 years. Postoperative infection affects up to 3% of patients and is the single most common reason for early return to theatre. Ultraclean ventilation was introduced to help mitigate the risk of infection, but it may also contribute to inadvertent perioperative hypothermia, which itself is a risk for postoperative infection. To counter this, active intraoperative warming is used for all procedures that take 30 min or more. Forced air warming (FAW) and resistive fabric warming (RFW) are the two principal techniques used for this purpose; they are equally effective in prevention of inadvertent perioperative hypothermia, but it is not known which is associated with the lowest infection rates. Deep surgical site infection doubles operative costs, triples investigation costs and quadruples ward costs. The Reducing Implant Infection in Orthopaedics (RIIiO) study seeks to compare infection rates with FAW versus RFW after hemiarthroplasty for hip fracture. A cost-neutral intervention capable of reducing postoperative infection rates would likely lead to a change in practice, yield significant savings for the health economy, reduce overall exposure to antibiotics and improve outcomes following hip fracture in the elderly. The findings may be transferable to other orthopaedic implant procedures and to non-orthopaedic surgical specialties. ⋯ Hemiarthroplasty carries a risk of deep surgical site infection of approximately 3%. In order to provide 90% power to demonstrate an absolute risk reduction of 1%, using a 5% significance level, a full trial would need to recruit approximately 8630 participants. A pilot study is being conducted in the first instance to demonstrate that recruitment and data management strategies are appropriate and robust before embarking on a large multi-centre trial.
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Whiplash-associated disorders (WAD) as a consequence of a motor vehicle crash are a costly health burden in Western societies. Up to 50% of injured people do not fully recover. There have been numerous clinical trials and cohort studies conducted for WAD with many varied outcome measures used, making data pooling difficult and hindering meta-analysis. These issues could be addressed through the development of a core outcome set (COS) that should be included in all clinical trials for WAD. The purpose of this project is to develop and disseminate a COS for clinical trials in WAD. ⋯ The aim of this proposal is to complete a five-stage process to develop a COS for all clinical trials in WAD. An implementation strategy will also be proposed.
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In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. ⋯ Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock.