Isabelle L Smith

Pressure RElieving Support SUrfaces: a Randomised Evaluation 2 (PRESSURE 2): study protocol for a randomised controlled trial

BackgroundPressure ulcers represent a major burden to patients, carers and the healthcare system, affecting approximately 1 in 17 hospital and 1 in 20 community patients. They impact greatly on an individual’s functional status and health-related quality of life. The mainstay of pressure ulcer prevention practice is the provision of pressure redistribution support surfaces and patient repositioning. The aim of the PRESSURE 2 study is to compare the two main mattress types utilised within the NHS: high-specification foam and alternating pressure mattresses, in the prevention of pressure ulcers.Methods/DesignPRESSURE 2 is a multicentre, open-label, randomised, double triangular, group sequential, parallel group trial. A maximum of 2954 ‘high-risk’ patients with evidence of acute illness will be randomised on a 1:1 basis to receive either a high-specification foam mattress or alternating-pressure mattress in conjunction with an electric profiling bed frame. The primary objective of the trial is to compare mattresses in terms of the time to developing a new Category 2 or above pressure ulcer by 30 days post end of treatment phase. Secondary endpoints include time to developing new Category 1 and 3 or above pressure ulcers, time to healing of pre-existing Category 2 pressure ulcers, health-related quality of life, cost-effectiveness, incidence of mattress change and safety. Validation objectives are to determine the responsiveness of the Pressure Ulcer Quality of Life-Prevention instrument and the feasibility of having a blinded endpoint assessment using photography. The trial will have a maximum of three planned analyses with unequally spaced reviews at event-driven coherent cut-points. The futility boundaries are constructed as non-binding to allow a decision for stopping early to be overruled by the Data Monitoring and Ethics Committee.DiscussionThe double triangular, group sequential design of the PRESSURE 2 trial will provide an efficient design through the possibility of early stopping for demonstrating either superiority, inferiority of mattresses or futility of the trial. The trial optimises the potential for producing robust clinical evidence on the effectiveness of two commonly used mattresses in clinical practice earlier than in a conventional design.Trial registrationISRCTN01151335. Registered on 14 May 2013. Protocol version: 5.0, dated 25 September 2015Trial sponsor: Clare Skinner, Faculty Head of Research Support, University of Leeds, Leeds, LS2 9JT; 0113 343 4897; C.E.Skinner@leeds.ac.uk.

The INVEST project: Investigating the use of evidence synthesis in the design and analysis of clinical trials

BackgroundWhen designing and analysing clinical trials, using previous relevant information, perhaps in the form of evidence syntheses, can reduce research waste. We conducted the INVEST (INVestigating the use of Evidence Synthesis in the design and analysis of clinical Trials) survey to summarise the current use of evidence synthesis in trial design and analysis, to capture opinions of trialists and methodologists on such use, and to understand any barriers.MethodsOur sampling frame was all delegates attending the International Clinical Trials Methodology Conference in November 2015. Respondents were asked to indicate (1) their views on the use of evidence synthesis in trial design and analysis, (2) their own use during the past 10 years and (3) the three greatest barriers to use in practice.ResultsOf approximately 638 attendees of the conference, 106 (17%) completed the survey, half of whom were statisticians. Support was generally high for using a description of previous evidence, a systematic review or a meta-analysis in trial design. Generally, respondents did not seem to be using evidence syntheses as often as they felt they should. For example, only 50% (42/84 relevant respondents) had used a meta-analysis to inform whether a trial is needed compared with 74% (62/84) indicating that this is desirable. Only 6% (5/81 relevant respondents) had used a value of information analysis to inform sample size calculations versus 22% (18/81) indicating support for this. Surprisingly large numbers of participants indicated support for, and previous use of, evidence syntheses in trial analysis. For example, 79% (79/100) of respondents indicated that external information about the treatment effect should be used to inform aspects of the analysis. The greatest perceived barrier to using evidence synthesis methods in trial design or analysis was time constraints, followed by a belief that the new trial was the first in the area.ConclusionsEvidence syntheses can be resource-intensive, but their use in informing the design, conduct and analysis of clinical trials is widely considered desirable. We advocate additional research, training and investment in resources dedicated to ways in which evidence syntheses can be undertaken more efficiently, offering the potential for cost savings in the long term.

Clinical Evaluation of a New Pressure Ulcer Risk Assessment Instrument, the Pressure Ulcer Risk Primary or Secondary Evaluation Tool (PURPOSE T)

Abstract Aim To test the psychometric properties and clinical usability of a new Pressure Ulcer Risk Assessment Instrument including inter‐rater and test–retest reliability, convergent validity and data completeness. Background Methodological and practical limitations associated with traditional Pressure Ulcer Risk Assessment Instruments, prompted a programme to work to develop a new instrument, as part of the National Institute for Health Research funded, Pressure UlceR Programme Of reSEarch (RP‐PG‐0407‐10056). Design Observational field test. Method For this clinical evaluation 230 patients were purposefully sampled across four broad levels of pressure ulcer risk with representation from four secondary care and four community NHS Trusts in England. Blinded and simultaneous paired (ward/community nurse and expert nurse) PURPOSE‐T assessments were undertaken. Follow‐up retest was undertaken by the expert nurse. Field notes of PURPOSE‐T use were collected. Data were collected October 2012–January 2013. Results The clinical evaluation demonstrated “very good” (kappa) inter‐rater and test–retest agreement for PURPOSE‐T assessment decision overall. The percentage agreement for “problem/no problem” was over 75% for the main risk factors. Convergent validity demonstrated moderate to high associations with other measures of similar constructs. Conclusion The PURPOSE‐T evaluation facilitated the initial validation and clinical usability of the instrument and demonstrated that PURPOSE‐T is suitable of use in clinical practice. Further study is needed to evaluate the impact of using the instrument on care processes and outcomes.

Using results from a UK-wide survey to justify choice of comparator for the treatment of severe chronic hand eczema

Treatment of severe chronic hand eczema (CHE) resistant to topical treatment with potent corticosteroids is challenging; in 2013 the Health Technology Assessment Programme released a commissioned call to investigate the most effective treatment for this disease with Alitretinoin specified as the active intervention to evaluate. Existing evidence on systemic treatment options with special focus on Alitretinoin has been summarised in an Evidence Review Groups Report on Alitretinoin for the treatment of severe CHE. The report highlighted that although Alitretinoin has demonstrated efficacy, data are lacking in terms of comparison to other treatment approaches. The brief required applicants to justify the choice of control intervention; we designed a survey to obtain information on currently used treatment pathways in the UK. A total of 194 UK Dermatologists responded and the results indicated that treatment approaches for severe CHE differ widely among UK dermatologists. PUVA(40.2%) and Alitretinoin(30.9%) were identified as the most frequent first line treatment options for hyperkeratotic CHE, whereas oral steroids(37.6%) were identified as the most commonly used for vesicular CHE, followed by PUVA(26.3%) and Alitretinoin(15.5%). In terms of potential side effects of long term or repeated use, Ciclosporine A(58.2%) and oral steroids(41.2%) were reported to cause most concerns among the surveyed dermatologists. The ALPHA team used the survey results to justify the use of PUVA as the control intervention for first line treatment and to evaluate second line treatments as a secondary objective. The ALPHA trial was approved for funding and is due to open to recruitment in October 2015.

Testosterone replacement in young male cancer survivors (TRYMS) - pragmatic adaptation of trial design for a trial struggling with recruitment

TRYMS is a multicentre, randomised, double-blinded, parallel group, placebo controlled phase IV trial in young male cancer survivors with low testosterone levels. The trial is designed to investigate whether testosterone treatment for 26 weeks will result in a reduction of truncal fat mass and increase in participant-reported physical functioning scores. The general consensus worldwide is that testosterone levels ≤12nmol/L are deemed to be low; however a previous study of 200 healthy volunteers found that testosterone≤10nmol/L would be deemed to be low. The trial team considered only including patients with testosterone≤10nmol/L but acknowledged this would leave an evidence gap for patients with testosterone between 10-12nmol/L. Therefore TRYMS was designed to determine whether testosterone replacement is effective in men with low testosterone and with borderline low testosterone by powering the study to look at each subgroup individually. A sample size of 268 participants was required after accounting for imbalanced recruitment to the subgroups. However, opening TRYMS took longer than anticipated and recruitment was substantially slower than expected; the trial design was adapted to combine the subgroups for primary analysis, reducing the minimum sample size to 112 participants. The trial was granted a recruitment extension and continued to recruit beyond the minimum sample size to maximise precision of the treatment effect estimates in each subgroup; this analysis is exploratory but still considered useful to inform clinical practice. This adaption of the trial design was a pragmatic approach for a trial struggling with recruitment, whilst still able to provide clinically useful results.

Assessing the accuracy of routinely collected data and their potential use in pressure ulcer trials.

Pressure ulcer trials often use development of category≥2 pressure ulcers as an endpoint[1]. Research nurses regularly assess patients skin to capture pressure ulcer development, however missed assessments may lead to missed pressure ulcers and capturing data from routine care may be an alternative. Pressure ulcer monitoring systems have been introduced in the English NHS including the Safety Thermometer. A project, funded by the Tissue Viability Society and supported by NHS England, comprised a pressure ulcer/wound audit to assess the accuracy of current monitoring systems. The pressure ulcer/wound audit was conducted on the Safety Thermometer census date (October 2014) in a stratified random sample of Trusts providing in-patient services in England, using ‘gold-standard’ prevalence methods[2]. In addition the Trust audit lead completed a questionnaire to elicit information about local practice for pressure ulcer reporting. The results show low accuracy of routine pressure ulcer data sources; the weighted sensitivity estimate(95% CI) for the safety thermometer was 48.2%(35.4%-56.7%). The pressure ulcer/wound audit indicated that pressure ulcers reported on monitoring systems may not be readily obtained from clinical notes. These results support published data comparing ward and research nurse data[1]. Questionnaire responses indicated there was variation across Trusts in terms of pressure ulcer reporting across all monitoring systems. Therefore, results of the pressure ulcer/wound audit and questionnaire indicate that current routine data sources for pressure ulcer monitoring would not be satisfactory for use in pressure ulcer trials.

Independent endpoint event review for the elimination of reporting bias in an open label phase III pharmaceutical trial

Background Open label randomised controlled trials may be subject to bias where outcome ascertainment relies on treating clinician decisions. In the setting of a multinational randomised controlled open label phase three pharmaceutical trial we implemented a rigorous verification algorithm to mitigate against such bias. We report the impact of the algorithm’s application on the primary endpoint.

TRYMS: the ethical and practical considerations of a double-blind placebo controlled randomised clinical trial

A double blind randomised trial is the gold standard approach to minimise the introduction of bias from trial participants, healthcare professionals and clinical trial staff. Similarly, the use of a placebo is ideal when participant self-reported Quality of Life is one of the primary objectives. However, the combination of these trial design components can present challenging ethical and practical issues for good trial conduct. TRYMS is a randomised, double-blinded, placebo controlled phase IV clinical trial in young male cancer survivors with low testosterone levels. The trial is designed to investigate whether testosterone treatment will result in a reduction of truncal fat mass and an increase in participant self-reported physical functioning scores and recruited 136 participants from 10 centres across the UK. Practical issues relate to the potential for centre and trials unit staff to be unblinded by access to clinical data: for example, retests of testosterone measurements required for dose titration were required in the active arm but were done in the placebo arm to maintain the blind. Other issues relate to managing Investigational Medicinal Product supply requirements: a minimisation programme is used to ensure treatment groups are well-balanced by randomising centre however, a random element and participant replenishment halfway during treatment can result in a temporary skew to a centre’s IMP requirements. The ethical issues relate to non-emergency requests for unblinding due to participant perception of treatment allocation. Our experiences in TRYMS, along with our solutions, will be presented with considerations for the management of similar trials.