Making large scale surgical trials possible:collaboration and the role of surgical trainees

Abstract Background Recruitment to surgical randomised controlled trials (RCTs) can be challenging. The Sunflower study is a large-scale multi-centre RCT that seeks to establish the clinical and cost effectiveness of pre-operative imaging versus expectant management in patients with symptomatic gallstones undergoing laparoscopic cholecystectomy at low or moderate risk of common bile duct stones. Trials such as Sunflower, with a large recruitment target, rely on teamworking. Recruitment can be optimised by embedding a QuinteT Recruitment Intervention (QRI). Additionally, engaging surgical trainees can contribute to successful recruitment, and the NIHR Associate Principal Investigator (API) scheme provides a framework to acknowledge their contributions. Methods This was a mixed-methods study that formed a component part of an embedded QRI for the Sunflower RCT. The aim of this study was to understand factors that supported and hindered the participation of surgical trainees in a large-scale RCT and their participation in the API scheme. It comprised semi-structured telephone interviews with consultant surgeons and surgical trainees involved in screening and recruitment of patients, and descriptive analysis of screening and recruitment data. Interviews were analysed thematically to explore the perspectives of—and roles undertaken by—surgical trainees. Results Interviews were undertaken with 34 clinicians (17 consultant surgeons, 17 surgical trainees) from 22 UK hospital trusts. Surgical trainees contributed to patient screening, approaches and randomisation, with a major contribution to the randomisation of patients from acute admissions. They were often encouraged to participate in the study by their centre principal investigator, and career development was a typical motivating factor for their participation in the study. The study was registered with the API scheme, and a majority of the trainees interviewed (n = 14) were participating in the scheme. Conclusion Surgical trainees can contribute substantial activity to a large-scale multi-centre RCT. Benefits of trainee engagement were identified for trainees themselves, for local sites and for the study as a whole. The API scheme provided a formal framework to acknowledge engagement. Ensuring that training and support for trainees are provided by the trial team is key to optimise success for all stakeholders

Improving the inclusion of an under-served group in trials: development and implementation of the INCLUDE Impaired Capacity to Consent Framework

Background: For the potential benefits of trials to reach all that they should, trials must be designed to ensure that those taking part reflect the population who will receive the intervention. However, adults with impaired capacity to consent are frequently excluded from trials — partly because researchers are unfamiliar with the legal and ethical frameworks and lack the necessary methodological expertise. Researchers identified a need for guidance on designing more inclusive trials. Building on the NIHR INCLUDE initiative, we developed the INCLUDE Impaired Capacity to Consent Framework to help researchers design inclusive trials. Methods: The framework was developed over five phases: (1) establishing the scope and content of the framework and adapting the INCLUDE Ethnicity Framework for this population; (2) scoping the relevance of the framework to different populations and piloting in a range of trials; (3) consulting people living with impairing conditions and carers to explore their views about the framework and identify missing content areas; (4) refining the framework; and (5) the development of an implementation toolkit of resources to support researchers using the framework. Results: The framework has two parts: a set of four key questions to help researchers identify who should be included in their trial, and a series of worksheets covering intervention design, recruitment and consent processes, data collection and analysis, and public involvement and dissemination. It is supported by a summary of the ethical and legal frameworks and a website of resources on capacity and consent. Implementation resources include infographics and animations, a library of completed frameworks, and facilitated workshops for researchers. The framework and toolkit were launched at a webinar (November 2022), with polling demonstrating an increase in attendees’ awareness about research involving adults lacking capacity. A post-webinar survey found that stakeholders viewed the framework and toolkit as valuable tools to facilitate greater inclusion of this under-served population in trials. The framework is available online: https://www.capacityconsentresearch.com/include-impaired-capacity-to-consent-framework.html. Conclusions: The INCLUDE Impaired Capacity to Consent Framework and implementation toolkit can support researchers to design more inclusive trials and other types of research studies. Further engagement, including with funders who are key to ensuring uptake, and evaluation is needed

Design and implementation of a large and complex trial in emergency medical services

Background: The research study titled “Cluster randomised trial of the clinical and cost effectiveness of the i-gel supraglottic airway device versus tracheal intubation in the initial airway management of out-of-hospital cardiac arrest (AIRWAYS-2)” is a large-scale study being run in the English emergency medical (ambulance) services (EMS). It compares two airway management strategies (tracheal intubation and the i-gel) in out-of-hospital cardiac arrest. We describe the methods used to minimise bias and the challenges associated with the set-up, enrolment, and follow-up that were addressed. Methods: AIRWAYS-2 enrols adults without capacity when there is no opportunity to seek prior consent and when the intervention must be delivered immediately. We therefore adopted a cluster randomised design where the unit of randomisation is the individual EMS provider (paramedic). However, because paramedics could not be blinded to the intervention, it was necessary to automatically enrol all eligible patients in the study to avoid bias. Effective implementation required engagement with four large EMS and 95 receiving hospitals. Very high levels of data capture were required to ensure study integrity, and this necessitated collaborative working across multiple organisations. We sought to manage these processes by using a large and comprehensive electronic study database, implementing efficient trial procedures and comprehensive training. Results: Successful implementation of the study design was facilitated by the approaches used. The necessary regulatory and ethical approvals to conduct the study were secured, and benefited from strong patient and public involvement. Early and continued consultation with decision makers within the four participating EMS resulted in a coordinated approach to study set-up. All receiving hospitals gave approval and agreed to collect data. A comprehensive database and programme of training and support were implemented. More than 1500 paramedics have been recruited to the study, and patient enrolment and follow-up has proceeded as planned. Conclusion: Care provided by EMS needs to be based on evidence. Although participants may be experiencing life-threatening emergencies, high-quality pre-hospital research is possible in well-designed and well-managed studies. The approaches described here can be used to support successful research that will lead to improved treatment and outcomes in similar patient groups. Trial registration: ISRCTN08256118. Registered on 22 July 2014

Validation of the Bluebelle Wound Healing questionnaire (WHQ) for assessment of surgical site infection in primary surgical wounds after hospital discharge

Background Accurate assessment of surgical‐site infection (SSI) is crucial for surveillance and research. Self‐reporting patient measures are needed because current SSI tools are limited for assessing patients after leaving hospital. The Bluebelle Wound Healing Questionnaire (WHQ) was developed for patient or observer completion; this study tested its acceptability, scale structure, reliability and validity in patients with closed primary wounds after abdominal surgery. Methods Patients completed the WHQ (self‐assessment) within 30 days after leaving hospital and returned it by post. Healthcare professionals completed the WHQ (observer assessment) by telephone or face‐to‐face. Questionnaire response rates and patient acceptability were assessed. Factor analysis and Cronbach's α examined scale structure and internal consistency. Test–retest and self‐ versus observer reliability assessments were performed. Sensitivity and specificity for SSI discrimination against a face‐to‐face reference diagnosis (using Centers for Disease Control and Prevention criteria) were examined. Results Some 561 of 792 self‐assessments (70·8 per cent) and 597 of 791 observer assessments (75·5 per cent) were completed, with few missing data or problems reported. Data supported a single‐scale structure with strong internal consistency (α greater than 0·8). Reliability between test–retest and self‐ versus observer assessments was good (κ 0·6 or above for the majority of items). Sensitivity and specificity for SSI discrimination was high (area under the receiver operating characteristic (ROC) curve 0·91). Conclusion The Bluebelle WHQ is acceptable, reliable and valid with a single‐scale structure for postdischarge patient or observer assessment of SSI in closed primary wounds

Getting our ducks in a row:The need for data utility comparisons of healthcare systems data for clinical trials

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS.METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status.DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.</p

Getting our ducks in a row:The need for data utility comparisons of healthcare systems data for clinical trials

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS.METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status.DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.</p

Randomized trial of the i-gel supraglottic airway device versus tracheal intubation during out of hospital cardiac arrest (AIRWAYS-2): Patient outcomes at three and six months

© 2020 The Author(s) Aim: The AIRWAYS-2 cluster randomised controlled trial compared the i-gel supraglottic airway device (SGA) with tracheal intubation (TI) as the first advanced airway management (AAM) strategy used by Emergency Medical Service clinicians (paramedics) treating adult patients with non-traumatic out-of-hospital cardiac arrest (OHCA). It showed no difference between the two groups in the primary outcome of modified Rankin Scale (mRS) score at 30 days/hospital discharge. This paper reports outcomes to 6 months. Methods: Paramedics from four ambulance services in England were randomised 1:1 to use an i-gel SGA (759 paramedics) or TI (764 paramedics) as their initial approach to AAM. Adults who had a non-traumatic OHCA and were attended by a participating paramedic were enrolled automatically under a waiver of consent. Survivors were invited to complete questionnaires at three and six months after OHCA. Outcomes were analysed using regression methods. Results: 767/9296 (8.3%) enrolled patients survived to 30 days/hospital discharge and 317/767 survivors (41.3%) consented and were followed-up to six months. No significant differences were found between the two treatment groups in the primary outcome measure (mRS score: 3 months: odds ratio (OR) for good recovery (i-gel/TI, OR) 0.89, 95% CI 0.69–1.14; 6 months OR 0.91, 95% CI 0.71–1.16). EQ-5D-5L scores were also similar between groups and sensitivity analyses did not alter the findings. Conclusion: There were no statistically significant differences between the TI and i-gel groups at three and six months. We therefore conclude that the initially reported finding of no significant difference between groups at 30 days/hospital discharge was sustained when the period of follow-up was extended to six months

The RELIEF feasibility trial: Topical lidocaine patches in older adults with rib fractures

Background: Lidocaine patches, applied over rib fractures, may reduce pulmonary complications in older patients. Known barriers to recruiting older patients in emergency settings necessitate a feasibility trial. We aimed to establish whether a definitive randomised controlled trial (RCT) evaluating lidocaine patches in older patients with rib fracture(s) was feasible. Methods: This was a multicentre, parallel-group, open-label, feasibility RCT in seven hospitals in England and Scotland. Patients aged ≥65 years, presenting to ED with traumatic rib fracture(s) requiring hospital admission were randomised to receive up to 3×700 mg lidocaine patches (Ralvo), first applied in ED and then once daily for 72 hours in addition to standard care, or standard care alone. Feasibility outcomes were recruitment, retention and adherence. Clinical end points (pulmonary complications, pain and frailty-specific outcomes) and patient questionnaires were collected to determine feasibility of data collection and inform health economic scoping. Interviews and focus groups with trial participants and clinicians/research staff explored the understanding and acceptability of trial processes. Results: Between October 23, 2021 and October 7, 2022, 206 patients were eligible, of whom 100 (median age 83 years; IQR 74–88) were randomised; 48 to lidocaine patches and 52 to standard care. Pulmonary complications at 30 days were determined in 86% of participants and 83% of expected 30-day questionnaires were returned. Pulmonary complications occurred in 48% of the lidocaine group and 59% in standard care. Pain and some frailty-specific outcomes were not feasible to collect. Staff reported challenges in patient compliance, unfamiliarity with research measures and overwhelming the patients with research procedures. Conclusion: Recruitment of older patients with rib fracture(s) in an emergency setting for the evaluation of lidocaine patches is feasible. Refinement of data collection, with a focus on the collection of pain, frailty-specific outcomes and intervention delivery are needed before progression to a definitive trial. Trial registration number: ISRCTN14813929

Safety and immunogenicity of concomitant administration of COVID-19 vaccines (ChAdOx1 or BNT162b2) with seasonal influenza vaccines in adults in the UK (ComFluCOV): a multicentre, randomised, controlled, phase 4 trial

Background: Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine.Methods: In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248.Findings: Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebo –1·29%, 95% CI –14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, –6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (–12·9%, –34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, –13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, –5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, –11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected.Interpretation: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need