Publications by authors named "Paula R Williamson"

193 Publications

An international core outcome set for evaluating interventions to improve informed consent to clinical trials: the ELICIT Study.

J Clin Epidemiol 2021 Feb 27. Epub 2021 Feb 27.

Health Services Research Unit, University of Aberdeen, Health Sciences Building, Foresterhill, Aberdeen, AB25 2ZB. Katie Gillies Senior Research Fellow, Vikki Entwistle Professor, Heid Gardner Research Fellow, Shaun Treweek Professor, Marion K Campbell Professor.

Objective: To develop a core outcome set for the evaluation of interventions that aim to improve how people make decisions about whether to participate in RCTs (of healthcare interventions), the ELICIT Study.

Study Design: International mixed-method study involving a systematic review of existing outcomes, semi-structured interviews, an online Delphi survey, and a face-to-face consensus meeting..

Results: The literature review and stakeholder interviews (n=25) initially identified 1045 reported outcomes that were grouped into 40 individually distinct outcomes. These 40 outcomes were scored for importance in two rounds of an online Delphi survey (n=79), with 18 people attending the consensus meeting. Consensus was reached on 12 core outcomes: therapeutic misconception; comfort with decision; authenticity of decision; communication about the trial; empowerment; sense of altruism; equipoise; knowledge; salience of questions; understanding, how helpful the process was for decision making; and trial attrition.

Conclusion: The ELICIT core outcome set is the first internationally agreed minimum set of outcomes deemed essential to be measured in all future studies evaluating interventions to improve decisions about participating in an RCT. Use of the ELICIT core set will ensure that results from these trials are comparable and relevant to all stakeholders.

Registration: COMET database - http://www.comet-initiative.org/Studies/Details/595.
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http://dx.doi.org/10.1016/j.jclinepi.2021.02.020DOI Listing
February 2021

Choosing important health outcomes for comparative effectiveness research: 6th annual update to a systematic review of core outcome sets for research.

PLoS One 2021 12;16(1):e0244878. Epub 2021 Jan 12.

Department of Health Data Science, University of Liverpool, Liverpool, United Kingdom.

Background: An annual update to a systematic review of core outcome sets (COS) for research ensures that the COMET database is up-to-date. The aims of this study were to: (i) identify COS that were published or indexed in 2019 and to describe the methodological approaches used in these studies; (ii) investigate whether children have been included as participants in published COS development studies, and which methods have been used to facilitate their participation; iii) update a previous exercise to identify COS relevant to the most burdensome global diseases and injuries.

Methods: MEDLINE and SCOPUS were searched to identify studies published or indexed between (and inclusive of) January 2019 and December 2019. Automated screening methods were used to rank the citations in order of relevance; the top 25% in ranked priority order were screened for eligibility. COS were assessed against each of the Core Outcome Set-STAndards for Development (COS-STAD). A search of the COMET database was undertaken to identify COS relevant to the 25 leading causes of disease burden.

Results: Thirty-three studies, describing the development of 37 COS, were included in this update. These studies have been added to the COMET database, which now contains 370 published (1981-2019) COS studies for clinical research. Six (18%) of the 33 studies in this update were deemed to have met all of the minimum standards for COS development (range = 4 to 12 criteria, median = 9 criteria). Of the 370 COS studies published to date, 82 COS have been developed for paediatric health conditions and children would have been eligible to participate in 68/82 of these studies. Eleven of these 68 (16%) COS studies have included children as participants within the development process, most commonly through participation in Delphi surveys. Relevant COS were identified for 22/25 leading causes of global disease burden.

Conclusion: There has been a demonstrated increase in COS developed for both research and routine practice, and consistently high inclusion of patient participants. COS developed for paediatric conditions need to further incorporate the perspectives of children, alongside parents and other adults, and adopt research methods fit for this purpose. COS developers should consider the gaps identified in this update as priorities for COS development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244878PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802923PMC
January 2021

Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery.

Crit Care Med 2021 03;49(3):503-516

College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

Objectives: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019.

Design: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery.

Setting: International.

Patients: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops.

Interventions: None.

Measurements And Main Results: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed.

Conclusions: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.
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http://dx.doi.org/10.1097/CCM.0000000000004817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892260PMC
March 2021

A randomised controlled trial comparing palate surgery at 6 months versus 12 months of age (the TOPS trial): a statistical analysis plan.

Trials 2021 Jan 4;22(1). Epub 2021 Jan 4.

Liverpool Clinical Trials Centre, University of Liverpool, a member of Liverpool Health Partners, Institute of Child Health, Alder Hey Children's NHS Foundation Trust, Liverpool, L12 2AP, UK.

Background: Cleft palate is among the most common birth abnormalities. The success of primary surgery in the early months of life is crucial for successful feeding, hearing, dental development, and facial growth. Over recent decades, age at palatal surgery in infancy has reduced. The Timing Of Primary Surgery for cleft palate (TOPS) trial aims to determine whether, in infants with cleft palate, it is better to perform primary surgery at age 6 or 12 months (corrected for gestational age).

Methods/design: The TOPS trial is an international, two-arm, parallel group, randomised controlled trial. The primary outcome is insufficient velopharyngeal function at 5 years of age. Secondary outcomes, measured at 12 months, 3 years, and 5 years of age, include measures of speech development, safety of the procedure, hearing level, middle ear function, dentofacial development, and growth. The analysis approaches for primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The TOPS protocol has been published previously.

Discussion: This paper provides details of the planned statistical analyses for the TOPS trial and will reduce the risk of outcome reporting bias and data-driven results.

Trial Registration: ClinicalTrials.gov NCT00993551 . Registered on 9 October 2009.
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http://dx.doi.org/10.1186/s13063-020-04886-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780678PMC
January 2021

Outcomes Evaluated in Controlled Clinical Trials on the Management of COVID-19: A Methodological Systematic Review.

Life (Basel) 2020 Dec 15;10(12). Epub 2020 Dec 15.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester M23 9LT, UK.

It is crucial that randomized controlled trials (RCTs) on the management of coronavirus disease 2019 (COVID-19) evaluate the outcomes that are critical to patients and clinicians, to facilitate relevance, interpretability, and comparability. This methodological systematic review describes the outcomes evaluated in 415 RCTs on the management of COVID-19, that were registered with ClinicalTrials.gov, by 5 May 2020, and the instruments used to measure these outcomes. Significant heterogeneity was observed in the selection of outcomes and instruments. Mortality, adverse events and treatment success or failure are only evaluated in 64.4%, 48.4% and 43% of the included studies, respectively, while other outcomes are selected less often. Studies focusing on more severe presentations (hospitalized patients or requiring intensive care) most frequently evaluate mortality (72.5%) and adverse events (55.6%), while hospital admission (50.8%) and viral detection/load (55.6%) are most frequently assessed in the community setting. Outcome measurement instruments are poorly reported and heterogeneous. Follow-up does not exceed one month in 64.3% of these earlier trials, and long-term COVID-19 burden is rarely assessed. The methodological issues identified could delay the introduction of potentially life-saving treatments in clinical practice. Our findings demonstrate the need for greater consistency, to enable decision makers to compare and contrast studies.
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http://dx.doi.org/10.3390/life10120350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765224PMC
December 2020

Can harmonisation of outcomes bridge the translation gap for pre-clinical research? A systematic review of outcomes measured in mouse models of type 2 diabetes.

J Transl Med 2020 12 9;18(1):468. Epub 2020 Dec 9.

Department of Health Data Science, University of Liverpool, Liverpool, L69 3GL, UK.

Background: In pre-clinical research, systematic reviews have the potential to mitigate translational challenges by facilitating understanding of how pre-clinical studies can inform future clinical research. Yet their conduct is encumbered by heterogeneity in the outcomes measured and reported, and those outcomes may not always relate to the most clinically important outcomes. We aimed to systematically review outcomes measured and reported in pre-clinical in vivo studies of pharmacological interventions to treat high blood glucose in mouse models of type 2 diabetes.

Methods: A systematic review of pre-clinical in vivo studies of pharmacological interventions aimed at addressing elevated blood glucose in mouse models of type 2 diabetes was completed. Studies were screened for eligibility and outcomes extracted from the included studies. The outcomes were recorded verbatim and classified into outcome domains using an existing outcome taxonomy. Outcomes were also compared to those identified in a systematic review of registered phase 3/4 clinical trials for glucose lowering interventions in people with type 2 diabetes.

Results: Review of 280 included studies identified 532 unique outcomes across 19 domains. No single outcome, or domain, was measured in all studies and only 132 (21%) had also been measured in registered phase 3/4 clinical trials. A core outcome set, representing the minimum that should be measured and reported, developed for type 2 diabetes effectiveness clinical trials includes 18 core outcomes, of these 12 (71%) outcomes were measured and reported in one or more of the included pre-clinical studies.

Conclusions: There is heterogeneity of outcomes reported in pre-clinical research. Harmonisation of outcomes across the research pathway using a core outcome set may facilitate interpretation, evidence synthesis and translational success, and may contribute to the refinement of the use of animals in research. Systematic review registration: The study was prospectively registered on the PROSPERO Database, registration number CRD42018106831.
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http://dx.doi.org/10.1186/s12967-020-02649-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727210PMC
December 2020

Onabotulinum toxin-A versus extended release tolterodine in the management of idiopathic overactive bladder in children: A pilot randomised controlled trial (OVERT trial).

J Pediatr Urol 2021 Feb 19;17(1):77.e1-77.e12. Epub 2020 Oct 19.

Royal Manchester Children's Hospital, UK. Electronic address:

Background: Idiopathic Overactive Bladder is the most common cause of urinary incontinence in children. Anticholinergic medications are successful in only 20% of those with daily wetting so there is a real need to find a more effective treatment for this condition. Onabotulinum toxin A injections are often used as a treatment but there have been no randomised controlled trials investigating effectiveness in children.

Objective: To provide information that would inform the design and conduct of a definitive trial comparing onabotulinum toxin A with extended-release tolterodine for the management of therapy resistant idiopathic overactive bladder in children. Specific objectives were to assess rates of eligibility, recruitment, acceptability of randomisation, loss to follow-up, acceptability of urodynamic assessment and obtain primary outcome data for sample size estimation.

Study Design: Single-centre, parallel, two-arm, open-label pilot randomised controlled trial. Eligible patients (aged 7-16 years) were recruited at Royal Manchester Children's Hospital and randomised (1:1) using a web-based system.

Trial Registration: EudraCT 2014-001068-36; Funding: UK NIHR Research for Patient Benefit Programme.

Results: 98 patients were assessed for eligibility, 85 (87%) were eligible for screening, parents of 62 (73%) provided consent, 46 (74%) remained eligible and were randomised (onabotulinum = 22, tolterodine = 24). All participants commenced allocated treatment. Two patients withdrew from follow-up. All participants underwent urodynamic assessment at baseline and 35 (76%) additionally at week 6. The mean (standard deviation) number of wetting episodes per day at week 6 was 1.4 (1.7) in the onabotulinum group and 1.6 (1.0) in the tolterodine group. There was one serious adverse event (probably related to the drug) and 22 non-serious adverse events reported by 8 participants in the onabotulinum group (36%). There were 23 non-serious adverse events reported by 9 participants in the tolterodine group (38%).

Discussion: Recruitment was challenging but eligibility and consent rates were high as were retention rates. Treatment compliance in the botox group was high but it was difficult to measure in the tolterodine group. Treatment switching was also an issue.

Conclusions: Recruitment to a definitive trial was demonstrated to be feasible if a large number of centres are involved, though further consideration is required regarding trial design.
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http://dx.doi.org/10.1016/j.jpurol.2020.10.012DOI Listing
February 2021

Use of routinely collected data in a UK cohort of publicly funded randomised clinical trials.

F1000Res 2020 4;9:323. Epub 2020 May 4.

MRC North West Hub for Trials Methodology Research, Department of Biostatistics, University of Liverpool, Liverpool, UK.

Routinely collected data about health in medical records, registries and hospital activity statistics is now routinely collected in an electronic form. The extent to which such sources of data are now being routinely accessed to deliver efficient clinical trials, is unclear. The aim of this study was to ascertain current practice amongst a United Kingdom (UK) cohort of recently funded and ongoing randomised controlled trials (RCTs) in relation to sources and use of routinely collected outcome data. Recently funded and ongoing RCTs were identified for inclusion by searching the National Institute for Health Research journals library. Trials that have a protocol available were assessed for inclusion and those that use or plan to use routinely collected health data (RCHD) for at least one outcome were included. RCHD sources and outcome information were extracted. Of 216 RCTs, 102 (47%) planned to use RCHD. A RCHD source was the sole source of outcome data for at least one outcome in 46 (45%) of those 102 trials. The most frequent sources are Hospital Episode Statistics (HES) and Office for National Statistics (ONS), with the most common outcome data to be extracted being on mortality, hospital admission, and health service resource use. Our study has found that around half of publicly funded trials in a UK cohort (NIHR HTA funded trials that had a protocol available) plan to collect outcome data from routinely collected data sources. This is much higher than the figure of 8% found in a cohort of 189 RCTs published since 2000, the majority of which were carried out in North America (McCord ., 2019).
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http://dx.doi.org/10.12688/f1000research.23316.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607478PMC
May 2020

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.

F1000Res 2020;9:1193. Epub 2020 Oct 2.

Meta-Research Innovation Center at Stanford (METRICS), Stanford University,, Stanford, California, USA.

: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.
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http://dx.doi.org/10.12688/f1000research.26707.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539080PMC
November 2020

"Vicarious thinking" was a key driver of score change in Delphi surveys for COS development and is facilitated by feedback of results.

J Clin Epidemiol 2020 Dec 1;128:118-129. Epub 2020 Oct 1.

MRC/NIHR Trials Methodology Research Partnership, Department of Biostatistics, Block F Waterhouse Building, University of Liverpool, 1-5 Brownlow Street, Liverpool L69 3GL, UK.

Objective: The objectives of this nested study were to (1) assess whether changes in scores between rounds altered the final degree of consensus achieved in three Delphi surveys conducted as part of COS development projects (anal, gastric, and prostate cancer), and (2) explore participants' reasons for changing scores between rounds.

Study Design And Setting: All Delphi surveys were conducted online using DelphiManager software and included healthcare professionals and participating patients. Participants were invited to give a free-text reason whenever they changed their score across an important threshold on a 1-9 Likert scale (1-3 not important, 4-5 important, 7-9 critically important). Reasons for score change were coded by four researchers independently using an inductive-iterative approach.

Results: In all three Delphi surveys, the number of outcomes reaching criteria for consensus was greater in R2 than R1. Twelve themes and 23 subthemes emerged from 2298 discrete reasons given for score change. The most common reasons for the change were "time to reflect" (482 responses, 23%) and vicarious thinking (424, 21%), with 68% (291) of vicarious thinking attributed to seeing other participant's scores.

Conclusion: Our findings support conducting a Delphi survey over the use of a single questionnaire where building consensus is the objective. Time to reflect and vicarious thinking, facilitated by seeing other participant's scores, were important drivers of score change. How results are presented to participants between rounds and the duration of and time between rounds in a Delphi survey may, therefore, influence the results and should be clearly reported.
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http://dx.doi.org/10.1016/j.jclinepi.2020.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716748PMC
December 2020

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

Lancet Respir Med 2020 10;8(10):975-986

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool Health Partners, Liverpool, UK.

Background: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa.

Methods: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10.

Findings: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group.

Interpretation: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis.

Funding: National Institute for Health Research Health Technology Assessment Programme.
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http://dx.doi.org/10.1016/S2213-2600(20)30331-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606906PMC
October 2020

A systematic review finds Core Outcome Set uptake varies widely across different areas of health.

J Clin Epidemiol 2021 Jan 26;129:114-123. Epub 2020 Sep 26.

MRC North West Hub for Trials Methodology Research, Department of Health Data Science, University of Liverpool, Block F Waterhouse Building, 1-5 Brownlow Street, Liverpool L69 3GL, United Kingdom.

Objective: The aim of our review was to bring together studies that had assessed the uptake of core outcome sets (COS) to explore the level of uptake across different COS and areas of health.

Study Design And Setting: We examined the citations of 337 COS reports to identify studies that had assessed the uptake of a particular COS in randomized controlled trials (RCTs) or systematic reviews (SRs).

Results: We identified 24 studies that had assessed uptake in RCTs and two studies that had assessed uptake in SRs. The studies covered a total of 17/337 (5%) COS. Uptake rates reported for RCTs varied from 0% of RCTs (gout) to 82% RCTs (rheumatoid arthritis) measuring the full COS. Studies that assessed uptake of individual core outcomes showed a wide variation in uptake between the outcomes. Suggested barriers to uptake included lack of validated measures, lack of patient and other key stakeholder involvement in COS development, and lack of awareness of the COS.

Conclusions: Few studies have been undertaken to assess the uptake of COS in RCTs and SRs. Further studies are needed to assess whether COS have been implemented across a wider range of disease categories and to explore the barriers and facilitators to COS uptake.
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http://dx.doi.org/10.1016/j.jclinepi.2020.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815247PMC
January 2021

Core outcome set for the management of acute exacerbations of chronic obstructive pulmonary disease: the COS-AECOPD ERS Task Force study protocol.

ERJ Open Res 2020 Jul 14;6(3). Epub 2020 Sep 14.

Section of Respiratory Medicine, Dept of Internal Medicine, Herlev-Gentofte Hospital, Hellerup, Denmark.

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.
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http://dx.doi.org/10.1183/23120541.00193-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487360PMC
July 2020

Assessing the relevance and uptake of core outcome sets (an agreed minimum collection of outcomes to measure in research studies) in Cochrane systematic reviews: a review.

BMJ Open 2020 09 6;10(9):e036562. Epub 2020 Sep 6.

Center for Evidence-based Healthcare, Medizinische Fakultät, Technische Universität Dresden, Dresden, Germany.

Objectives: A core outcome set (COS) is an agreed standardised minimum collection of outcomes that should be measured and reported in research in a specific area of health. Cochrane systematic reviews ('reviews') are rigorous reviews on health-related topics conducted under the auspices of Cochrane. This study examines the use of existing COS to inform the choice of outcomes in Cochrane systematic reviews ('reviews') and investigates the views of the coordinating editors of Cochrane Review Groups (CRGs) on this topic.

Methods: A cohort of 100 recently published or updated Cochrane reviews were assessed for reference to a COS being used to inform the choice of outcomes for the review. Existing COS, published 2 or more years before the review publication, were then identified to assess how often a reviewer could have used a relevant COS if it was available. We asked 52 CRG coordinating editors about their involvement in COS development, how outcomes are selected for reviews in their CRG and their views of the advantages and challenges surrounding the standardisation of outcomes within their CRG.

Results: In the cohort of reviews from 2019, 40% (40/100) of reviewers noted problems due to outcome inconsistency across the included studies. In 7% (7/100) of reviews, a COS was referenced in relation to the choice of outcomes for the review. Relevant existing COS could be considered for a review update in 35% of the others (33/93). Most editors who responded (31/36, 86%) thought that COS should definitely or possibly be used to inform the choice of outcomes in a review.

Conclusions: Systematic reviewers are continuing to note outcome heterogeneity but are starting to use COS to inform their reviews. There is potential for greater uptake of COS in Cochrane reviews.
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http://dx.doi.org/10.1136/bmjopen-2019-036562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476465PMC
September 2020

Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs (SANAD-II).

BMJ Open 2020 08 26;10(8):e040635. Epub 2020 Aug 26.

Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK

Introduction: Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service (NHS) use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide.

Methods And Analysis: This is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Arm A of the trial randomised 990 patients with focal epilepsy to standard AED lamotrigine or new AED levetiracetam or zonisamide. Arm B randomised 520 patients with generalised epilepsy to standard AED sodium valproate or new AED levetiracetam. Patients are recruited from UK NHS outpatient epilepsy, general neurology and paediatric clinics. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to 12-month remission from seizures. Secondary outcomes include time to treatment failure (including due to inadequate seizure control or unacceptable adverse reactions); time to first seizure; time to 24-month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED.

Ethics And Dissemination: This trial has been approved by the North West-Liverpool East REC (Ref. 12/NW/0361). The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement.

Trial Registration Numbers: EudraCT 2012-001884-64; ISRCTN30294119.
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http://dx.doi.org/10.1136/bmjopen-2020-040635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451282PMC
August 2020

Core Outcomes Set for Trials in People With Coronavirus Disease 2019.

Crit Care Med 2020 11;48(11):1622-1635

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Objectives: The outcomes reported in trials in coronavirus disease 2019 are extremely heterogeneous and of uncertain patient relevance, limiting their applicability for clinical decision-making. The aim of this workshop was to establish a core outcomes set for trials in people with suspected or confirmed coronavirus disease 2019.

Design: Four international online multistakeholder consensus workshops were convened to discuss proposed core outcomes for trials in people with suspected or confirmed coronavirus disease 2019, informed by a survey involving 9,289 respondents from 111 countries. The transcripts were analyzed thematically. The workshop recommendations were used to finalize the core outcomes set.

Setting: International.

Subjects: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public and health professionals (including clinicians, policy makers, regulators, funders, researchers).

Interventions: None.

Measurements: None.

Main Results: Six themes were identified. "Responding to the critical and acute health crisis" reflected the immediate focus on saving lives and preventing life-threatening complications that underpinned the high prioritization of mortality, respiratory failure, and multiple organ failure. "Capturing different settings of care" highlighted the need to minimize the burden on hospitals and to acknowledge outcomes in community settings. "Encompassing the full trajectory and severity of disease" was addressing longer term impacts and the full spectrum of illness (e.g. shortness of breath and recovery). "Distinguishing overlap, correlation and collinearity" meant recognizing that symptoms such as shortness of breath had distinct value and minimizing overlap (e.g. lung function and pneumonia were on the continuum toward respiratory failure). "Recognizing adverse events" refers to the potential harms of new and evolving interventions. "Being cognizant of family and psychosocial wellbeing" reflected the pervasive impacts of coronavirus disease 2019.

Conclusions: Mortality, respiratory failure, multiple organ failure, shortness of breath, and recovery are critically important outcomes to be consistently reported in coronavirus disease 2019 trials.
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http://dx.doi.org/10.1097/CCM.0000000000004585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448717PMC
November 2020

International Survey to Establish Prioritized Outcomes for Trials in People With Coronavirus Disease 2019.

Crit Care Med 2020 11;48(11):1612-1621

College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

Objectives: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials.

Design: In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7-9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically.

Setting: International.

Subjects: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers).

Interventions: None.

Measurements: None.

Main Results: In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean > 7.5, median ≥ 8, and > 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences; addressing knowledge gaps; enabling preparedness and planning; and tolerable or infrequent outcomes.

Conclusions: Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.
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http://dx.doi.org/10.1097/CCM.0000000000004584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448718PMC
November 2020

Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study.

Health Technol Assess 2020 07;24(36):1-152

Alder Hey Children's NHS Foundation Trust, a member of the Liverpool Health Partners, Liverpool, UK.

Background: In the UK, juvenile idiopathic arthritis is the most common inflammatory disorder in childhood, affecting 10 : 100,000 children and young people aged < 16 years each year, with a population prevalence of around 1 : 1000. Corticosteroids are commonly used to treat juvenile idiopathic arthritis; however, there is currently a lack of consensus as to which corticosteroid induction regimen should be used with various disease subtypes and severities of juvenile idiopathic arthritis.

Objective: The main study objective was to determine the feasibility of conducting a randomised controlled trial to compare the different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis.

Design: This was a mixed-methods study. Work packages included a literature review; qualitative interviews with children and young people with juvenile idiopathic arthritis and their families; a questionnaire survey and screening log to establish current UK practice; a consensus meeting with health-care professionals, children and young people with juvenile idiopathic arthritis, and their families to establish the primary outcome; a feasibility study to pilot data capture and to collect data for future sample size calculations; and a final consensus meeting to establish the final protocol.

Setting: The setting was rheumatology clinics across the UK.

Participants: Children, young people and their families who attended clinics and health-care professionals took part in this mixed-methods study.

Interventions: This study observed methods of prescribing corticosteroids across the UK.

Main Outcome Measures: The main study outcomes were the acceptability of a future trial for children, young people, their families and health-care professionals, and the feasibility of delivering such a trial.

Results: Qualitative interviews identified differences in the views of children, young people and their families on a randomised controlled trial and potential barriers to recruitment. A total of 297 participants were screened from 13 centres in just less than 6 months. In practice, all routes of corticosteroid administration were used, and in all subtypes of juvenile idiopathic arthritis. Intra-articular corticosteroid injection was the most common treatment. The questionnaire surveys showed the varying clinical practice across the UK, but established intra-articular corticosteroids as the treatment control for a future trial. The primary outcome of choice for children, young people, their families and health-care professionals was the Juvenile Arthritis Disease Activity Score, 71-joint count. However, results from the feasibility study showed that, owing to missing blood test data, the clinical Juvenile Arthritis Disease Activity Score should be used. The Juvenile Arthritis Disease Activity Score, 71-joint count, and the clinical Juvenile Arthritis Disease Activity Score are composite disease activity scoring systems for juvenile arthritis. Two final trial protocols were established for a future randomised controlled trial.

Limitations: Fewer clinics were included in this feasibility study than originally planned, limiting the ability to draw strong conclusions about these units to take part in future research.

Conclusions: A definitive randomised controlled trial is likely to be feasible based on the findings from this study; however, important recommendations should be taken into account when planning such a trial.

Future Work: This mixed-methods study has laid down the foundations to develop the evidence base in this area and conducting a randomised control trial to compare different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis is likely to be feasible.

Study Registration: Current Controlled Trials ISRCTN16649996.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 36. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443738PMC
July 2020

Standardising definitions for the pre-eclampsia core outcome set: A consensus development study.

Pregnancy Hypertens 2020 Jul 20;21:208-217. Epub 2020 Jun 20.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.

Objectives: To develop consensus definitions for the core outcome set for pre-eclampsia.

Study Design: Potential definitions for individual core outcomes were identified across four formal definition development initiatives, nine national and international guidelines, 12 Cochrane systematic reviews, and 79 randomised trials. Eighty-six definitions were entered into the consensus development meeting. Ten healthcare professionals and three researchers, including six participants who had experience of conducting research in low- and middle-income countries, participated in the consensus development process. The final core outcome set was approved by an international steering group.

Results: Consensus definitions were developed for all core outcomes. When considering stroke, pulmonary oedema, acute kidney injury, raised liver enzymes, low platelets, birth weight, and neonatal seizures, consensus definitions were developed specifically for low- and middle-income countries because of the limited availability of diagnostic interventions including computerised tomography, chest x-ray, laboratory tests, equipment, and electroencephalogram monitoring.

Conclusions: Consensus on measurements for the pre-eclampsia core outcome set will help to ensure consistency across future randomised trials and systematic reviews. Such standardization should make research evidence more accessible and facilitate the translation of research into clinical practice. Video abstract can be available at: www.dropbox.com/s/ftrgvrfu0u9glqd/6.%20Standardising%20definitions%20in%20teh%20pre-eclampsia%20core%20outcome%20set%3A%20a%20consensus%20development%20study.mp4?dl=0.
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http://dx.doi.org/10.1016/j.preghy.2020.06.005DOI Listing
July 2020

A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT.

Health Technol Assess 2020 06;24(32):1-142

Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool (a member of Liverpool Health Partners), Liverpool, UK.

Background: Relatives caring for people with severe mental health problems find information and emotional support hard to access. Online support for self-management offers a potential solution.

Objective: The objective was to determine the clinical effectiveness and cost-effectiveness of an online supported self-management tool for relatives: the Relatives' Education And Coping Toolkit (REACT).

Design And Setting: This was a primarily online (UK), single-blind, randomised controlled trial, comparing REACT plus a resource directory and treatment as usual with the resource directory and treatment as usual only, by measuring user distress and other well-being measures at baseline and at 12 and 24 weeks.

Participants: A total of 800 relatives of people with severe mental health problems across the UK took part; relatives who were aged ≥ 16 years, were experiencing high levels of distress, had access to the internet and were actively seeking help were recruited.

Intervention: REACT comprised 12 psychoeducation modules, peer support through a group forum, confidential messaging and a comprehensive resource directory of national support. Trained relatives moderated the forum and responded to messages.

Main Outcome Measure: The main outcome was the level of participants' distress, as measured by the General Health Questionnaire-28 items.

Results: Various online and offline strategies, including social media, directed potential participants to the website. Participants were randomised to one of two arms: REACT plus the resource directory ( = 399) or the resource directory only ( = 401). Retention at 24 weeks was 75% (REACT arm,  = 292; resource directory-only arm,  = 307). The mean scores for the General Health Questionnaire-28 items reduced substantially across both arms over 24 weeks, from 40.2 (standard deviation 14.3) to 30.5 (standard deviation 15.6), with no significant difference between arms (mean difference -1.39, 95% confidence interval -3.60 to 0.83;  = 0.22). At 12 weeks, the General Health Questionnaire-28 items scores were lower in the REACT arm than in the resource directory-only arm (-2.08, 95% confidence interval -4.14 to -0.03;  = 0.027), but this finding is likely to be of limited clinical significance. Accounting for missing data, which were associated with higher distress in the REACT arm (0.33, 95% confidence interval -0.27 to 0.93;  = 0.279), in a longitudinal model, there was no significant difference between arms over 24 weeks (-0.56, 95% confidence interval -2.34 to 1.22;  = 0.51). REACT cost £142.95 per participant to design and deliver (£62.27 for delivery only), compared with £0.84 for the resource directory only. A health economic analysis of NHS, health and Personal Social Services outcomes found that REACT has higher costs (£286.77), slightly better General Health Questionnaire-28 items scores (incremental General Health Questionnaire-28 items score adjusted for baseline, age and gender: -1.152, 95% confidence interval -3.370 to 1.065) and slightly lower quality-adjusted life-year gains than the resource directory only; none of these differences was statistically significant. The median time spent online was 50.8 minutes (interquartile range 12.4-172.1 minutes) for REACT, with no significant association with outcome. Participants reported finding REACT a safe, confidential environment (96%) and reported feeling supported by the forum (89%) and the REACT supporters (86%). No serious adverse events were reported.

Limitations: The sample comprised predominantly white British females, 25% of participants were lost to follow-up and dropout in the REACT arm was not random.

Conclusions: An online self-management support toolkit with a moderated group forum is acceptable to relatives and, compared with face-to-face programmes, offers inexpensive, safe delivery of National Institute for Health and Care Excellence-recommended support to engage relatives as peers in care delivery. However, currently, REACT plus the resource directory is no more effective at reducing relatives' distress than the resource directory only.

Future Work: Further research in improving the effectiveness of online carer support interventions is required.

Trial Registration: Current Controlled Trials ISRCTN72019945.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 32. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355407PMC
June 2020

Core outcome sets through the healthcare ecosystem: the case of type 2 diabetes mellitus.

Trials 2020 Jun 25;21(1):570. Epub 2020 Jun 25.

Department of Health Data Science, University of Liverpool (a member of Liverpool Health Partners), Liverpool, UK.

Background: It is increasingly accepted that insufficient attention has been given to the patient health outcomes that are important to measure in comparative effectiveness research that will inform decision-making. The relationship between outcomes chosen for comparative effectiveness research, outcomes used in decision-making in routine care, and outcome data recorded in electronic health records (EHR) is also poorly understood. The COMET Initiative (http://www.comet-initiative.org/. Accessed 3 Apr 2020) supports and encourages the development and use of 'core outcome sets' (COS), which represent the minimum set of patient health outcomes that should be measured and reported for a specific condition. There is growing interest in identifying how COS might fit into the different stages of the healthcare research and delivery ecosystem, and whether inclusion in the EHR might facilitate this.

Methods: We sought to determine the degree of overlap between outcomes within COS for research and routine care, EMA, FDA and NICE guidelines, NICE quality statements/indicators, EHR and a point-of-care randomised clinical trial, using type 2 diabetes (T2D) as a case study.

Results: There is substantial agreement about important patient outcomes for T2D for research and healthcare, with associated coverage within the UK general practice EHR.

Conclusions: This case study has demonstrated the potential for efficient research and value-based healthcare when the EHR can include COS for both research and care, where the COS comprises outcomes of importance to all relevant stakeholders. However, this concordance may not hold more generally, as the focus on patient-centred outcomes may well be greater in T2D than in other conditions. Work is ongoing to examine other clinical areas, in order to highlight any current inefficiencies when health outcomes in research and healthcare do not agree with core outcomes identified by patients, clinicians and other key stakeholders.
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http://dx.doi.org/10.1186/s13063-020-04403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318375PMC
June 2020

Core outcome set for nonpharmacological community-based interventions for people living with dementia at home: A Systematic Review of Outcome Measurement Instruments.

Gerontologist 2020 Jun 25. Epub 2020 Jun 25.

Faculty of Health and Medicine, Division of Health Research, Lancaster University, Lancaster, UK.

Background And Objectives: It is questionable whether existing outcome measurement instruments (OMIs) in dementia research reflect what key stakeholders' value. We attained consensus from over 300 key stakeholders, including people living with dementia, and identified 13 core outcome items for use in nonpharmacological and community-based interventions for people with dementia living at home. In this systematic review we review OMIs that have previously been used in dementia care research to determine how, or even if, the 13 core outcome items can be measured.

Research Design And Methods: We extracted self-reported OMIs from trials, reviews and reports of instrument development. Searches were undertaken in the ALOIS database, Medline, PsycINFO, CINAHL, socINDEX and COSMIN database. We aimed to assess the psychometric properties of OMI items for face validity with the core outcome items, content validity, internal consistency and responsiveness. We held a co-research workshop involving people living with dementia and care partners in order to ratify the findings.

Results: In total 347 OMIs were located from 354 sources. Of these 76 OMIs met the inclusion criteria. No OMIs were deemed to have sufficient face validity for the COS items, and no OMIs proceeded to further assessment. The 'best' available OMI is the Engagement and Independence in Dementia Questionnaire (EID-Q).

Discussion And Implications: This study provides a practical resource for those designing dementia research trials. Being able to measure the COS items would herald a paradigm shift for dementia research, be responsive to what key stakeholders value and enhance the ability to make comparisons.
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http://dx.doi.org/10.1093/geront/gnaa071DOI Listing
June 2020

Methods used in the selection of instruments for outcomes included in core outcome sets have improved since the publication of the COSMIN/COMET guideline.

J Clin Epidemiol 2020 09 26;125:64-75. Epub 2020 May 26.

Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Objectives: Once a core outcome set (COS) has been defined, it is important to achieve consensus on how these outcomes should be measured. The aims of this systematic review were to gain insight into the methods used to select outcome measurement instruments and to determine whether methods have improved following the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)/Core Outcome Measures in Effectiveness Trials (COMET) guideline publication.

Study Design And Setting: Eligible articles, which were identified from the annual COMET systematic review, concerned any COS development studies that provided a recommendation on how to measure the outcomes included in the COS. Data were extracted on the methods used to select outcome measurement instruments in accordance with the COSMIN/COMET guideline.

Results: Of the 118 studies included in the review, 48% used more than one source of information when finding outcome measurement instruments, and 74% performed some form of quality assessment of the measurement instruments. Twenty-three studies recommended one single instrument for each core outcome included in the COS. Clinical experts and public representatives were involved in selecting instruments in 62% and 28% of studies, respectively.

Conclusion: Methods used to select outcome measurement instruments have improved since the publication of the COSMIN/COMET guideline. Going forward, COS developers should ensure that recommended outcome measurement instruments have sufficient content validity. In addition, COS developers should recommend one instrument for each core outcome to contribute to the overarching goal of uniformity in outcome reporting.
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http://dx.doi.org/10.1016/j.jclinepi.2020.05.021DOI Listing
September 2020

Core outcome set measurement for future clinical trials in acute myeloid leukemia: the HARMONY study protocol using a multi-stakeholder consensus-based Delphi process and a final consensus meeting.

Trials 2020 May 27;21(1):437. Epub 2020 May 27.

Charité University Medicine, Chariteplatz 1, Berlin, 10117, Germany.

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has an unacceptably low cure rate. In recent years, a number of new treatment strategies and compounds were developed for the treatment of AML. There were several randomized controlled clinical trials with the objective to improve patients' management and patients' outcome in AML. Unfortunately, these trials are not always directly comparable since they do not measure the same outcomes, and currently there are no core outcome sets that can be used to guide outcome selection and harmonization in this disease area. The HARMONY (Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology) Alliance is a public-private European network established in 2017 and currently includes 53 partners and 32 associated members from 22 countries. Amongst many other goals of the HARMONY Alliance, Work Package 2 focuses on defining outcomes that are relevant to each hematological malignancy. Accordingly, this pilot study will be performed to define a core outcome set in AML.

Methods: The pilot study will use a three-round Delphi survey and a final consensus meeting to define a core outcome set. Participants will be recruited from different stakeholder groups, including patients, clinicians, regulators and members of the European Federation of Pharmaceutical Industries and Associations. At the pre-Delphi stage, a literature research was conducted followed by several semi-structured interviews of clinical public and private key opinion leaders. Subsequently, the preliminary outcome list was discussed in several multi-stakeholder face-to-face meetings. The Delphi survey will reduce the preliminary outcome list to essential core outcomes. After completion of the last Delphi round, a final face-to-face meeting is planned to achieve consensus about the core outcome set in AML.

Discussion: As part of the HARMONY Alliance, the pilot Delphi aims to define a core outcome set in AML on the basis of a multi-stakeholder consensus. Such a core outcome set will help to allow consistent comparison of future clinical trials and real-world evidence research and ensures that appropriate outcomes valued by a range of stakeholders are measured within future trials.
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http://dx.doi.org/10.1186/s13063-020-04384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251906PMC
May 2020

Controversy and Debate Series on Core Outcome Sets. Paper 4: Debate on Paper 1 from the perspective of COMET [Core Outcome Measures in Effectiveness Trials].

J Clin Epidemiol 2020 09 13;125:222-224. Epub 2020 May 13.

MRC-NIHR Trials Methodology Research Partnership, University of Liverpool, Liverpool L63 3GL, UK.

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http://dx.doi.org/10.1016/j.jclinepi.2020.05.014DOI Listing
September 2020

Usage Metrics of Web-Based Interventions Evaluated in Randomized Controlled Trials: Systematic Review.

J Med Internet Res 2020 04 16;22(4):e15474. Epub 2020 Apr 16.

Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.

Background: The evaluation of web-based interventions (defined as an intervention that can be downloaded or accessed on the internet through a web browser) in randomized controlled trials (RCTs) has increased over the past two decades. Little is known about how participants' use of the intervention is measured, reported, and analyzed in these studies.

Objective: This study aimed to review the evaluation of web-based interventions in RCTs, assessing study characteristics and the methods used to record, and adjust for, intervention usage.

Methods: A systematic review of the literature was undertaken to identify all published reports of RCTs that involved a web-based intervention. A random sample of 100 published trials was selected for detailed data extraction. Information on trial characteristics was extracted, including whether web usage data were recorded, and if so, the methods used to gather these data and whether these data were used to inform efficacy analyses.

Results: A PubMed search identified 812 trials of web-based interventions published up to the end of 2017 and demonstrated a growing trend over time. Of the 100 studies reviewed, 90 studies collected web usage data, but more than half (49/90, 54%) of these studies did not state the method used for recording web usage. Only four studies attempted to check on the reliability of their web usage data collection methods. A total of 39% (35/90) studies reported patterns or levels of web intervention use, of which 21% (19/90) studies adjusted for intervention use in their outcome analysis, but only two of these used appropriate statistical methods.

Conclusions: Trialists frequently report a measure of web-based intervention usage but do not always report the collection method or provide enough detail on their analysis of web usage. Appropriate statistical methods to account for intervention use are rarely used and are not well reported even in the very few trials in which they are used. The number of trialists who attempt to check on the reliability of their web usage collection methods is extremely low.
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http://dx.doi.org/10.2196/15474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193439PMC
April 2020

Where next for inhaled corticosteroids in childhood asthma?

Lancet Respir Med 2020 04 21;8(4):345. Epub 2020 Jan 21.

Liverpool Clinical Trials Centre, Department of Biostatistics, University of Liverpool (a member of Liverpool Health Partners), Liverpool, UK.

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http://dx.doi.org/10.1016/S2213-2600(20)30013-8DOI Listing
April 2020

Cauda Equina Syndrome Core Outcome Set (CESCOS): An international patient and healthcare professional consensus for research studies.

PLoS One 2020 10;15(1):e0225907. Epub 2020 Jan 10.

Institute of Translational Medicine, University of Liverpool, Liverpool, Merseyside, United Kingdom.

Background: Cauda Equina Syndrome (CES) is an emergency condition that requires acute intervention and can lead to permanent neurological deficit in working age adults. A Core Outcome Set (COS) is the minimum set of outcomes that should be reported by a research study within a specific disease area. There is significant heterogeneity in outcome reporting for CES, which does not allow data synthesis between studies. The hypothesis is that a COS for CES can be developed for future research studies using patients and healthcare professionals (HCPs) as key stakeholders.

Methods And Findings: Qualitative semi-structured interviews with CES patients were audio-recorded, transcribed and analysed using NVivo to identify the outcomes of importance. These were combined with the outcomes obtained from a published systematic literature review of CES patients. The outcomes were grouped into a list of 37, for rating through two rounds of an international Delphi survey according to pre-set criteria. The Delphi survey had an overall response rate of 63% and included 172 participants (104 patients, 68 HCPs) from 14 countries who completed both rounds. Thirteen outcomes reached consensus at the end of the Delphi survey and there was no attrition bias detected. The results were discussed at an international consensus meeting attended by 34 key stakeholders (16 patients and 18 HCPs) from 8 countries. A further three outcomes were agreed to be included. There was no selection bias detected at the consensus meeting. There are 16 outcomes in total in the CESCOS.

Discussion: This is the first study in the literature that has determined the core outcomes in CES using a transparent international consensus process involving healthcare professionals and CES patients as key stakeholders. This COS is recommended as the most important outcomes to be reported in any research study investigating CES outcomes and will allow evidence synthesis in CES.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953762PMC
April 2020

Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed.

Trials 2020 Jan 7;21(1):33. Epub 2020 Jan 7.

Northern Ireland Methodology Hub, Queen's University Belfast, Belfast, UK.

The evidence base available to trialists to support trial process decisions-e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants-is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process.SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste.This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.
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http://dx.doi.org/10.1186/s13063-019-3980-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945587PMC
January 2020

Selecting Core Outcomes for Randomised Effectiveness trials In Type 2 diabetes (SCORE-IT): a patient and healthcare professional consensus on a core outcome set for type 2 diabetes.

BMJ Open Diabetes Res Care 2019 29;7(1):e000700. Epub 2019 Dec 29.

Department of Biostatistics, University of Liverpool, Liverpool, UK.

Objectives: Heterogeneity in outcomes measured across trials of glucose-lowering interventions for people with type 2 diabetes impacts on the ability to compare findings and may mean that the results have little importance to healthcare professionals and the patients that they care for. The SCORE-IT study (Selecting Core Outcomes for Randomised Effectiveness trials In Type 2 diabetes) has addressed this issue by establishing consensus on the most important outcomes for non-surgical interventions for hyperglycemia in type 2 diabetes.

Research Design And Methods: A comprehensive list of outcomes was developed from registered clinical trials, online patient resources, qualitative literature and long-term studies in the field. This list was then scored in a two-round online Delphi survey completed by healthcare professionals, people with type 2 diabetes, researchers in the field and healthcare policymakers. The results of this online Delphi were discussed and ratified at a face-to-face consensus meeting.

Results: 173 people completed both rounds of the online survey (116 people with type 2 diabetes, 37 healthcare professionals, 14 researchers and 6 policymakers), 20 of these attended the consensus meeting (13 people with type 2 diabetes and 7 healthcare professionals). Consensus was reached on 18 core outcomes across five domains, which include outcomes related to diabetes care, quality of life and long-term diabetes-related complications.

Conclusions: Implementation of the core outcome set in future trials will ensure that outcomes of importance to all stakeholders are measured and reported, enhancing the relevance of trial findings and facilitating the comparison of results across trials.
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http://dx.doi.org/10.1136/bmjdrc-2019-000700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936506PMC
August 2020