Trials

BackgroundThe Vision Impact Project (VIP) is a major community-based eye screening programme running in Kenya with the aim of promoting eye health for all. Previous studies embedded within the programme in Meru County have found that a third of people who are screened require care for an eye problem, however only half of these people manage to access outreach treatment clinics. Access varies between sociodemographic groups, and only 30% of young adults (18-44 years old) were able to access care. In previous mixed-methods work our team conducted interviews and surveys with non-attenders from this left-behind group to explore what could be done to improve access. MethodsYounger adults told us that better counselling at the point of referral would be likely to improve attendance rates. Based on their feedback, we have developed a script that will be read to participants in the intervention arm at the point of referral, and then sent as a reminder SMS the following day. We will assess whether attendance rates are higher among those randomised to receive this enhanced counselling compared to those who receive standard care. The primary outcome will be the proportion of people from the left-behind group who attend triage clinic. Our secondary analysis will examine overall mean attendance across all groups. We will calculate Bayesian posterior probabilities of attendance in each arm every seven days and continually recruit participants until one of two stopping rules have been met: there is a >95% probability that one arm is best or there is a >95% probability that the difference between the arms is <1%. DiscussionThis Bayesian RCT will be embedded into the clinical workflow software that is used to manage referrals and clinic attendance. It will test whether a simple, low-cost, service user-derived intervention is able to improve access to services among a population group that is currently being left behind. Trial RegistrationISRCTN 11329596, Registered on 02 February 2024 Administrative Information O_TBL View this table: org.highwire.dtl.DTLVardef@1d5f90forg.highwire.dtl.DTLVardef@d26da7org.highwire.dtl.DTLVardef@11d2ffdorg.highwire.dtl.DTLVardef@139a021org.highwire.dtl.DTLVardef@3ff4e7_HPS_FORMAT_FIGEXP M_TBL C_TBL

IntroductionAs a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low Anterior Resection Syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on Quality-of-Life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options. Methods and AnalysisThe objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of trans-anal irrigation (TAI) or sacral neural modulation (SNM) compared to optimised conservative management (OCM) for people with major LARS. POLARiS is a prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort (TWiCs design), with internal pilot phase, qualitative sub-study, process evaluation, and economic evaluation. Approximately 1500 adult participants from UK hospitals and 500 from Australian hospitals who have undergone a high or low anterior resection for colorectal cancer in the last 10 years will be recruited into the cohort. 600 participants from the UK and 200 participants from Australia, with major LARS symptoms, defined as a LARS score of [&ge;]30, will be recruited to the randomised controlled trial (RCT) element. Participants entering the RCT will be randomised between OCM, TAI or SNM, all with equal allocation ratios. Cohort and RCT participants will be followed up for a 24-month period, completing a series of questionnaires measuring LARS symptoms and QoL, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted. The primary outcome measure of the POLARiS cohort and RCT is the LARS score up to 24 months post registration/randomisation. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI vs OCM and SNM vs OCM. Secondary outcomes include health-related QoL, adverse events, treatment compliance and cost effectiveness (up to 24 months post registration/randomisation) Ethics and DisseminationEthical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants upon request and published on completion of the trial in a peer-reviewed journal and at international conferences Trial Registration NumberISRCTN12834598 Registered 04/08/2023 ACTRN12623001166662 Registered 10/11/2023 Strengths and LimitationsO_LIThe trial is pragmatically designed to optimise and assess recruitment and retainment. C_LIO_LIThis trial includes an economic evaluation of treatment options specific to both the UK and Australia. C_LIO_LILay representatives with personal experience of bowel cancer and LARS have contributed throughout the trial design and ongoing Trial Management Group meetings. C_LIO_LIThere are recognised potential limitations to the LARS score, including limited sensitivity to detect real time change in response to treatment. Additional outcome measures of Quality of Life and a new LARS Patient Reported Outcome Measure (PROM) are being collected to give a more nuanced picture of treatment response. C_LI

BackgroundChronic cardiovascular diseases (CVD) care quality remains suboptimal, globally. This study evaluated the feasibility and preliminary effect of a multicomponent, collaborative quality improvement (C-QIP) strategy among patients with CVD attending outpatient clinics in India. Methods and FindingsWe conducted a pragmatic feasibility randomized controlled trial in patients with ischemic heart disease, ischemic stroke or heart failure across public and private hospitals in India. Participants were individually randomized to C-QIP strategy (electronic decision support system, eDSS for providers, task-sharing with non-physician health workers, patient education, and SMS text reminders, and audit-feedback) or usual care. The primary outcomes were implementation measures: feasibility, fidelity, adoption, and acceptability from providers and patients perspectives. Secondary outcomes included prescription of guideline-directed medical therapy (GDMT), adherence to prescribed therapy, processes of care, and CVD risk factors. Of 410 participants enrolled (intervention arm=206 and usual care arm=204), mean age was 57.5 years, and 73.0% were male. Prior history of coronary heart disease was 74.6%, ischemic stroke: 18.5%, and heart failure: 18.0%. At trial end (mean follow-up 18 months), implementation outcomes were strong: retention at end-of-study was 192/206 (93.2%) in C-QIP and 187/204 (91.7%) in usual care arm; fidelity of the intervention remained high, e.g., 187/198 (94.4%) patients received lifestyle advice at end-of-study. Clinician adoption of eDSS prompts was high, and acceptance of DSS prompts varied by type of prompts, and both patients and providers reported high acceptability at trial end. GDMT use improved significantly in C-QIP vs usual care arm at end-of-study: in patients with ischemic heart disease use of antiplatelet + statin + ACEi/ARB + beta-blocker was 58.3% vs 32.4%, RR=1.45 (95%CI: 1.18-1.78); and among patients with ischemic stroke use of antiplatelet + statin + ACEi/ARB or diuretic was 76.7% vs 31.8%, RR=2.41 (95%CI: 1.52-3.81). GDMT among patients with heart failure were not different between groups (e.g., ACEi/ARB /ARNI + beta-blocker + MRA, 48.9% vs 48.6%, RR=1.26, 95%CI: 0.82-1.94). Patient adherence to prescribed therapy improved in C-QIP vs usual care arm: medications 90.9% vs 82.3%, RR 1.08 (1.04-1.12); diet plan 91.9% vs 82.3%, RR 1.07 (1.02-1.13); and physical activity 91.4% vs 70.4%, RR=1.23 (95%CI: 1.16-1.30). Processes of care improved significantly in C-QIP vs usual care arm, including more structured reminders (e.g., call after missed appointment 70.7% vs 4.4%, p<0.001) and longer clinician contact time (median 10 vs 7 minutes, p<0.001). CVD risk factors showed small, non-significant trends (e.g., modest diastolic BP reduction) for between-group differences in blood pressure, lipids and glycemia. ConclusionsThe C-QIP trial demonstrated that a multicomponent strategy is feasible, acceptable, and improved processes of chronic CVD care in India. Future large, confirmatory hybrid trials are needed to establish whether such quality improvement strategies can reduce cardiovascular morbidity and mortality. Trial RegistrationClinicaltrials.gov number: NCT05196659 Clinical Trials Registry India: CTRI/2022/04/041847

IntroductionRandomised controlled trials (RCTs) investigate the safety and efficacy of interventions. It has become clear however that some RCTs include fabricated data. The INSPECT-SR tool assesses the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. However, where individual participant data (IPD) can be obtained, a more thorough assessment of trustworthiness is possible. Consequently, INSPECT-SR recommends obtaining IPD to resolve uncertainties, though there is no consensus on appropriate methods for forensic analysis of raw data. Our aim is to evaluate IPD checks to establish which are worthwhile, and how they can be implemented in a new tool, INSPECT-IPD (Investigating Problematic Clinical Trials with Individual Participant Data). Methods and analysisUsing international expert consensus and empirical evidence, the INSPECT-IPD tool will be developed using five stages: (1) compiling a list of IPD trustworthiness checks, (2) evaluating the usefulness and ease of interpretation of the checks when applying them to a collection of presumed authentic and fabricated IPD datasets, (3) a Delphi survey to determine which checks are supported by expert consensus, (4) a series of consensus meetings for selection of checks to be included in the draft tool and finally (5) prospective testing of the draft tool in: a) the production of systematic reviews, and b) the journal editorial process for RCT submissions, leading to refinement based on user feedback. Ethics and disseminationThe University of Manchester ethics decision tool determined that ethical approval was not required (18 June 2024). This project includes secondary research and surveys of healthcare researchers on topics relating to their work. All results will be published as preprints and open-access articles, and the final tool will be freely available. STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIAn international consensus process and empirical evidence will be used to develop the tool. C_LIO_LIThe development and dissemination of the tool will involve key stakeholders. C_LIO_LIIn the absence of a gold-standard test for problematic data, this tool should not be interpreted as a diagnostic instrument for trustworthiness. Instead, it will assist researchers in assessing the trustworthiness of a study. C_LIO_LIThe tool will only be applicable when individual participant data (IPD) can be accessed. Where IPD can be accessed, the ability to assess trustworthiness will be improved. C_LI

The SToP trial is an (open-cohort) stepped-wedge cluster randomised trial (SWCRT) that aims to evaluate a skin health programme comprising three intervention components (1) seeing skin infections; (2) treating skin infections; and (3) preventing skin infections. Four community clusters in the remote Kimberley region of Western Australia will participate in the study. The primary outcome is the diagnosis of impetigo in children (5-9 years) observed during school-based surveillance visits. We provide a detailed, prospective statistical analysis plan (SAP). The plan was written by the trial statistician and details the study design as well as the statistical methods and reporting to be used. The SAP was produced prior to any of the authors viewing any of the trial data. Application of this SAP will minimise bias and supports transparent and reproducible research. SToP is registered under the Australian and New Zealand Clinical Trials Registry, ACTRN12618000520235.

IntroductionEndovenous therapy is the first-choice management for symptomatic varicose veins in NICE guidelines, with 56-70,000 procedures performed annually in the UK. Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), and endothermal heat-induced thrombosis (EHIT), are known complications of endovenous therapy, occurring at a rate of up to 3.4%. In an attempt to reduce VTE, 73% of UK practitioners administer pharmacological thromboprophylaxis. However, no high-quality evidence to support this practice exists. Pharmacological thromboprophylaxis may have clinical and cost benefit in preventing VTE, however, further evidence is needed. The aims of this study are to establish whether when endovenous therapy is undertaken: a single dose or course of pharmacological thromboprophylaxis alters the risk of VTE; pharmacological thromboprophylaxis is associated with an increased rate of bleeding events; pharmacological prophylaxis is cost effective. Methods and analysisA multi-centre, assessor-blind, randomised controlled trial (RCT). We aim to recruit 6660 participants undergoing superficial endovenous interventions under local anaesthesia. Forty sites across the UK, both NHS and private, will be included. Participants will be randomised to either intervention (a single dose or extended course of pharmacological thromboprophylaxis plus compression) or control (compression alone). Participants will undergo a lower limb venous duplex ultrasound scan at 21-28 days post-procedure to identify asymptomatic DVT. The ultrasound duplex scan will be conducted locally by blinded assessors. Participants will also be contacted remotely for follow-up at 7-days and 90-days post-procedure. The primary outcome is imaging confirmed lower limb DVT with or without symptoms, or PE with symptoms within 90 days of treatment. The main analysis will be according to the intention-to-treat principle and will compare the rates of VTE at 90 days, using a repeated measures analysis of variance (ANOVA), adjusting for any pre-specified strongly prognostic baseline covariates using a mixed effects logistic regression. Trial registration numberISRCTN18501431 ARTICLE SUMMARYStrengths and limitations of this study O_LIThe study will serve as a large, randomised controlled trial providing grade A evidence on the most clinically- and cost-effective thromboprophylaxis regimen following superficial endovenous treatment. C_LIO_LIThe primary outcome holds clinical significance. C_LIO_LIUsing VTE prophylaxis may be associated with adverse clinical outcomes, increased risks and may not be cost-effective. C_LIO_LIShould pharmacological thromboprophylaxis be shown to offer no additional benefit to patients undergoing superficial endovenous intervention, stopping this practice has the potential to generate significant cost savings for healthcare providers. C_LI

BackgroundInformed consent rates are inconsistently incorporated in trial reports, and literature on consent patterns and predictions is sparse, particularly in the field of critical care. ObjectiveThe overall objective of this study is to describe the patterns and predictors of consent rates in REVISE. The specific aims are to analyze the consent models used, consent rates, participants in the consent encounter, reasons for declined consent, and factors associated with obtaining consent. MethodsThis is a pre-planned secondary study of the REVISE Trial (NCT03374800) which compared pantoprazole to placebo on the outcome of clinically important upper gastrointestinal bleeding among invasively ventilated patients in the intensive care unit (ICU). Research ethics committees approved the protocol in all jurisdictions. Research personnel prospectively collected standardized data for each consent encounter, including the consent model (a priori, deferred, or opt-out), the role of the individual who provided or declined consent (patient, SDM, other), and the reasons for declined consent, the role of the individual who requested consent (research coordinator, site investigator, ICU physician) and the consent encounter method (in person or via telephone). When consent was provided and then later revoked, who revoked consent (patient, SDM, other) and timing (in ICU, in hospital, post hospital), as well as details about permission for data retention were collected. In this study, consent rates will be calculated across REVISE sites, and in relation to the COVID-19 pandemic. We will also calculate the consent rates for a priori and deferred consent models, the timing from deferred recruitment to consent provided or declined, which personnel requested consent (research coordinator, site investigator, ICU physicians, other), and who engaged in the consent encounter for each consent model (patient, SDM, other). Multilevel logistic regression analysis will be conducted to evaluate variables independently associated with consent including additional site and staff variables. ResultsBy analyzing the frequency and impact of consent models, and consent encounters with various stakeholders, results will highlight the acceptability of different approaches, and the impact of different approaches in this critical care trial. ConclusionsThis pre-planned retrospective sub-study using an international randomized controlled trial database will provide useful informed consent metrics and knowledge that is relevant to contemporary global trial conduct.

Knee osteoarthritis (OA) is common, painful, progressive and disabling, and has significant personal and societal burden, particularly in an ageing population. Whilst knee replacement is successful for very late stage disease, it is inappropriate for earlier stages, leaving few effective treatments available for patients in the "treatment gap" between symptom free and late-stage arthritis. High Tibial Osteotomy (HTO) is a proven surgical treatment providing good long-term outcome, reducing pain and improving function. HTO involves changing the alignment of the tibia to correct improper joint loading. Outcomes of HTO surgery are linked directly to the accuracy of the surgical re-alignment with under-correction resulting in worse outcomes. Inaccuracies occur primarily due to limitations of the current planning and surgical technique. A new method (TOKA) has been devised involving personalisation and digital planning. This method uses a custom personalised surgical guide and plate, tailored to the patient. The aim of the PASHiOn trial is to establish whether digitally planned personalised HTO surgery (TOKA) increases the accuracy of bone correction in comparison to conventional HTO surgery. Embedded within the trial is a nonrandomised pre-RCT technology check and safety assessment of 5 patients (Phase 1), followed by a randomised controlled trial of 88 patients (Phase 2). During Phase 1 of the clinical investigation, 5 patients fulfilling the inclusion criteria will be recruited and assessed in an identical way to the 88 patients recruited in the main trial, but without randomisation. Recruitment of the remaining patients (Phase 2) will take place after the six-week assessment on the fifth patient is complete and the oversight committee supports progression to Phase 2. Patients in Phase 1 and 2 will be followed up in the same manner for a period of up to 15 months from registration (Phase 1) and randomisation (Phase 2) (12 months from surgery).

Background: Statistical Analysis Plans (SAPs) are essential for trial transparency and credibility but are resource-intensive to produce. While Large Language Models (LLMs) have shown promise in drafting protocols, their ability to generate high-quality, protocol-compliant SAPs remains untested against current content guidance. This study developed and validated an LLM-based pipeline for drafting SAPs from clinical trial protocols. Methods: We developed a structured, section-by-section prompting pipeline aligned with standard SAP guidance. We applied this pipeline to nine clinical trial protocols using three leading LLMs: OpenAI GPT-5, Anthropic Claude Sonnet 4, and Google Gemini 2.5 Pro. The resulting 27 SAPs were evaluated against a 46-item quality checklist derived from the published SAP guidelines. Items were double-scored by independent trial statisticians on a 0 to 3 scale for accuracy. We compared performance across LLMs and between item types (descriptive vs. statistical reasoning) using mixed-effects logistic regression. Results: Across 9 trials, the models produced SAP drafts with high overall accuracy (77% to 78%), with no difference in performance between the three LLMs (p=0.79) but varied by content type (p < 0.001). All models performed well on descriptive items (e.g., administrative details, trial design), with lower accuracy for items requiring statistical reasoning (e.g., modelling strategies, sensitivity analyses). Accuracy for statistical items ranged from 67% to 72%, whereas descriptive items achieved 81% to 83% accuracy. Qualitatively, models were prone to specific failure modes in complex sections, such as omitting necessary details for secondary outcome models or hallucinating sensitivity analyses. Discussion: Current LLMs can effectively draft portions of SAPs, offering the potential for substantial time savings in trial documentation. However, a human-in-the-loop approach remains mandatory; while models demonstrate strong capability in producing descriptive content, their independent application to complex statistical methodology design still requires further methodological development and training. Future work should explore advanced prompt engineering, such as retrieval-augmented generation or agentic workflows, to improve reasoning capabilities.

BackgroundReproducing published findings from clinical trials is a critical component of scientific transparency, yet it remains a challenging and under-practiced task. Despite increasing emphasis on reproducibility and data reuse in research policies, few real-world examples exist where independent teams have reproduced complex analyses using clinical trial data. In this case study, the aim was to independently reproduce the key findings of a high-impact clinical trial on rectal cancer treatment using shared trial data. MethodWe organized a multi-team datathon, where each team was provided with the same dataset and supporting material, and was tasked to reproduce the results of the CAO/ARO/AIO-04 trial, with optional additional analysis. We contacted the original investigators for data access and reuse, and consulted them to understand the study, clinically and scientifically. ResultsFive teams used R or Python to reproduce the statistical results, and the corresponding scripts can be found on Gitlab. All teams reproduced the analyses for primary outcome--disease-free survival (DFS). The key findings on DFS were consistently reproduced, reinforcing confidence in the trial main conclusions. Result robustness was investigated using a different analytical software or statistical models. Nevertheless, challenges were encountered when the supplementary materials were not easily identified. Minor reporting issues were noticed in the reproduced paper. ConclusionReproduction of a major oncology clinical trial confirmed the reliability of its main conclusions. Divergences highlighted reporting gaps--such as incomplete protocols and broken links --that future trials should address. This case study demonstrates the value of systematic reproducibility checks for clinical research transparency and challenges in data sharing for reproducibility.

Background The prevalence of chronic heart failure is increasing in Singapore and is associated with frequent hospitalisations, high costs, and impaired quality of life. Patient empowerment interventions for chronic diseases, which are structured approaches that enable patients to actively engage in and influence their care, have demonstrated promising effects on health-related outcomes. In chronic heart failure, however, many interventions focus on selected aspects of empowerment, and there remains limited synthesis of which approaches are most acceptable, preferred, and effective as comprehensive intervention packages. This protocol describes the methods for a study to identify an empowerment-based intervention for adults with chronic heart failure that is both contextually suitable and cost-effective in Singapore. Methods We will use a staged, sequential design comprising three objectives. Objective one is to conduct a systematic review (PROSPERO registration number CRD420251249957) and meta-analysis to synthesise international evidence of the effectiveness of empowerment-based interventions for adults with chronic heart failure. Objective two is to complete a mixed-methods study, including semi-structured interviews with chronic heart failure patients, as well as their caregivers, to identify empowerment-related needs, barriers and facilitators in local chronic heart failure care. This will be followed by a discrete choice experiment to elicit patients preferences for features of an empowerment-based intervention. Objective three is to conduct a cost-effectiveness analysis of the proposed intervention from the perspective of the Singapore health system. Discussion This series of studies integrates international evidence with local stakeholder perspectives and patient preferences to inform a feasible, patient-centred empowerment intervention for chronic heart failure in Singapore. The findings will inform intervention design and provide policy-relevant evidence on costs, health outcomes, and implementation decisions for empowerment-based chronic heart failure care in Singapore.

BackgroundSince the Ghanaian National Health Insurance Scheme (NHIS) was introduced in 2004, coverage rates have remained low, despite affordable premiums and payment exemptions for minor, senior, poor and pregnant individuals. While 82% of the population have registered with the NHIS, many fail to complete the annual renewal and thus lose their coverage. A mobile renewal service introduced in 2018 simplified the previously cumbersome renewal procedure. Still, 40% of active member experience gaps in coverage in a given year, and 19% fail to renew at all. Baseline research suggests that forgetfulness is a major barrier to renewal. Methods342,818 NHIS members from Kumasi will be randomized into the reminder, autorenewal or control groups. The reminder arm receives SMS prompts to complete the mobile renewal process and payment before expiration. The autorenewal arm is eligible to sign up for automatic renewal and give the NHIS permission to deduct the premium from their mobile money account, and will receive SMS prompt to do so. The intervention lasts 6 months. NHIS routine data will be used to evaluate the effect of the interventions on renewals. A follow-up survey household survey in Kumasi will evaluate additional aspects user experience. DiscussionImproving insurance retention has the potential to substantially increase health insurance coverage rates, as 45% of the Ghanaians currently have expired insurance. Assessing these tools will identify enabling factors and barriers of the intervention and inform the transferability of the intervention to other health insurance systems in sub-Saharan African countries. Trial registrationPan African Clinical Trials Registry (PACTR)

BackgroundThe optimal model for delivering Tele-ICU is still to be determined. Previous clinical trials focused on medical-led daily multidisciplinary rounds (DMRs), showing certain improvements in processes of care but without direct evidence for improvement in clinical outcomes. ObjectiveTo evaluate whether a structured Tele-ICU intervention, comprising DMRs led by an intensivist plus a multidisciplinary care bundle (nursing, physical therapy, pharmacy) and a quality and safety management package, can reduce ICU length of stay in Brazilian public ICUs. MethodsThe TELESCOPE 2 is a multicenter, open-label, stepped-wedge cluster randomized controlled trial including 25 ICUs in Brazil from January 2024 to January 2026. In a stepped-wedge assignment, ICUs are randomized and allocated into one of five sequences. All adult patients admitted in participant ICUs will be eligible for inclusion in the study. Admissions for non-medical reasons, and patients previously included in the TELESCOPE 2 study will be excluded. All ICUs will receive the interventions staggered at different times. The trial intervention is multifaceted, comprising three components delivered in combination via telemedicine: i) daily multidisciplinary rounds led by board-certified intensive care physician; ii) coordinated care by a multidisciplinary team, including nurses, physiotherapists, and clinical pharmacists; iii) a management strategy focused on quality improvement and patient safety. The primary outcome is ICU length of stay. Secondary outcomes include clinical endpoints (ICU mortality, ventilator-free days at 28 days, and ventilator-associated events), process-of-care indicators (e.g., mobilization density, head-of-bed elevation, and sedation management), and unit-level organizational outcomes based on standard resource use and standardized mortality rates. ConclusionWe describe the statistical analysis plan for the TELESCOPE II trial, finalized prior to database lock. This pre-specified approach mitigates analysis bias and ensures the transparency and robustness of the reported results. TRIAL REGISTRATIONClinicaltrials NCT05960994, Brazilian Registry of Clinical Trials RBR-342wxn9, and Universal Trial Number U1111-1298-9799.

Background Traditional participant information and consent forms (PICFs) have changed little over time and are often lengthy and complex. A novel consent process incorporating plain language, an infographic brochure and a short explanatory video was developed to improve communication of clinical trial information. The SImPLE study was designed to evaluate whether this novel consent process improves comprehension of clinical trial information, participant engagement and the consent experience compared with a traditional PICF. Design and Setting SImPLE is a randomised two-period crossover study involving adults receiving cancer treatment who are potentially eligible for clinical trial participation. Study materials were developed for the ANZadapt (ANZUP2101) prostate cancer clinical trial; however, participants are not being recruited to ANZadapt itself. Participants are randomised to receive either a standard 17-page NHMRC-style PICF followed by a novel consent process, or the reverse sequence, with a washout period of at least 7 days between study periods. The novel consent process comprises a simplified 4-page PICF, infographic brochure and short explanatory video. Twenty-four hours following each PICF review, participants complete a comprehension assessment and structured interview. Outcomes and Endpoints The primary endpoint is comprehension of clinical trial information, measured using a study-specific 22-item questionnaire comprising 10 true/false and 12 multiple-choice questions. Secondary endpoints include acceptability, assessed through participant preference for communication format, and engagement, assessed through confidence in explaining the trial and likelihood of agreeing to participate. Planned Analyses The primary analysis will compare comprehension scores between the novel and standard consent approaches using a paired t-test among participants completing both study periods. Secondary outcomes relating to acceptability and engagement will be summarised descriptively and compared between consent approaches as appropriate. Sensitivity analyses will be performed to assess the robustness of the primary findings and the potential impact of crossover design effects.

Basket trial designs with interim analysis have gained significant attention due to their adaptability, flexibility, and scalability. In response to the need for user-friendly tools that enhance the real-world applicability of these designs, we developed a web-based interface aimed at facilitating two-stage basket trial designs. Built using R Shiny, the tool was rigorously validated for output consistency by comparing it to an established R pipeline. Additionally, user testing was conducted to ensure the interface is intuitive and easy to use. The result is a freely accessible tool that provides effective and convenient visualizations for general basket trial designs with interim analysis, available at https://desmondzeyachen.shinyapps.io/AdaptiveTwoStageBasketTrialFeb14/. Future improvements may further expand the tools capabilities to accommodate the increasing complexity of trial designs needed by the research community.

IntroductionDigital trials are a promising strategy to increase the evidence base for common interventions and may convey considerable efficiency benefits in trial conduct. Although paediatric intensive care units (PICUs) are rich in routine electronic data, highly pragmatic digital trials in this field remain scarce. There are unmet evidence needs for optimal mechanical ventilation modes in paediatric intensive care. We aim to test the feasibility of a digital PICU trial comparing two modes of invasive mechanical ventilation using carbon dioxide (CO2) control as the outcome measure. Methods and analysisSingle-centre, open-labelled, randomized controlled pilot trial with two parallel treatment arms comparing pressure control (PC) vs pressure-regulated volume control (PRVC). Patients are eligible if aged <18 years, weighing >2 kg, have an arterial line, and require >60 minutes of mechanical ventilation during PICU hospitalization at the University Childrens Hospital Zurich. Exclusion criteria include cardiac shunt lesions, pulmonary hypertension under treatment, and intracranial hypertension. CO2 is measured using three methods: end-tidal (continuous), transcutaneous (continuous), and blood gas analyses (intermittent). Baseline, intervention, and outcome data are collected electronically from the patients routine electronic health records. The primary feasibility outcome is adherence to the assigned ventilation mode, while the primary physiological outcome is the proportion of time spent within the target range of CO2 (end-tidal, normocarbia defined as CO2 [&ge;] 4.5, [&le;] 6 kPa). Both outcomes are captured digitally every minute from randomization until censoring (48 hours after randomization, extubation, discharge, or death, whichever comes first). Analysis will occur on an intention-to-treat basis. We aim to enrol 60 patients in total. Recruitment started in January 2024 and is planned to continue for 6 months. Ethics and disseminationThis study received ethical approval (BASEC 2022-00829). Study results will be disseminated through publication in a peer-reviewed journal and other media like podcasts. Trial registration numberNCT058431 ARTICLE SUMMARYO_LIThis study compares two commonly used modes of invasive mechanical ventilation in a randomized design. The trial will provide feasibility data to inform the conduct of digital trials by using electronic patient data directly extracted from the source systems, minimizing manual data collection and associated bias and thereby increasing local readiness for more efficient clinical trial conduct. C_LIO_LIOutcomes of this pilot trial relate to feasibility and physiological measures; future larger trials should also explore patient-centred outcomes. C_LIO_LIBlinding is not possible due to the nature of the intervention. C_LIO_LITechnical issues that may affect the availability or accuracy of data may arise and will be documented. C_LIO_LISome aspects of digital trials, such as electronic informed consent, are not implemented in this trial. C_LI

Representation of different groups at appropriate levels in clinical trials is of great importance. Factors affecting what appropriate levels include the demographics at the trial sites and the prevalence of the condition under study in different populations. We examined 359 trials published in New England Journal of Medicine, Journal of the American Medical Association (JAMA), and the Lancet in 2020 for information about Black participation rates. Sufficient information for analysis was available in 58 trials. Simulations including both site demographics and prevalence factors revealed that observed Black participation rates were reasonably well correlated with estimated potential Black participation rates, but that actual participation rates were lower than potential rates in 47 out of 58 trials. This approach could be used to estimate appropriate participation rates prior to trial initiation and for analysis of trials upon completion. Promotion of such transparency standards will aid future analyses and should help drive improvements in representation over time. Clinical trials represent important opportunities to test potential interventions in groups of individuals who can provide meaningful data and who represent populations who might benefit from the trial results. This has been described and highlighted by the recent report "Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups" from the United States National Academy of Sciences1. One of the overarching conclusions from this report is:

ObjectivesLate recognition of physiological deterioration is a frequent problem in hospital wards. We assessed whether ambulatory (wearable) physiological monitoring combined with a system that continuously merges physiological variables into a single "risk" score (VSI), changed care and outcome in patients after major surgery. DesignPre- and post-interventional study. SettingA single centre tertiary referral university hospital upper-gastrointestinal service. ParticipantsPatients who underwent major upper-gastrointestinal surgery. InterventionsPhase-I (pre-intervention phase): Patients received continuous wearable monitoring and standard care, but the VSI score was not available for clinical use. Phase-II (post-intervention phase): Patients received continuous wearable monitoring. In addition to standard care the VSI score was displayed for use in clinical practice. Measurements and Main Results200 participants were monitored in phase-I. 207 participants were monitored in phase-II. Participants were monitored (median, interquartile range, IQR) for 30.2% (13.8-49.2) of available time in phase-I and 58.2% (33.1-75.2) of available time in phase-II. Clinical staff recorded observations more frequently in the 36 hours prior to a major adverse event (death, cardiac arrest or unplanned admission to intensive care) for phase-II participants (median, IQR, time between observations of 1.00, 0.50-2.08 hours) than phase-I participants (1.50, 0.75-2.50 hours, p<0.001). There was no difference in observation frequency between the two phases for participants who did not undergo an adverse event (p=0.129). 6/200 participants died before hospital discharge in phase-I, 1/207 participants died in hospital in phase-II. 20 (10.0%) patients in phase-I and 26 (12.6%) patients in phase-II had an unplanned admission to intensive care. Ward length-of-stay was unaltered (8.91, 6.71-14.02 days in phase-I, vs. 8.97, 5.99-13.85 days in phase-II, p=0.327). ConclusionThe combination of the integrated monitoring system with ambulatory monitoring in high-risk post-surgical patients improved recognition and management of deteriorating patients without increasing the observation rate in those patients who did not deteriorate.

BackgroundRandomized trials evaluating emergency treatments may be conducted with Exception from Informed Consent (EFIC) when prospective informed consent is infeasible. In EFIC trials, a period of community consultation and public disclosure precedes initiation of enrollment. The Randomized Trial of Sedative Choice for Intubation (RSI) is a 2,364-patient randomized trial being conducted with EFIC in 14 emergency departments and intensive care units across the United States. This manuscript reports the approach to community consultation and public disclosure in the RSI trial. MethodsCommunity consultation and public disclosure were conducted locally in each of the 5 regions of enrolling sites. The coordinating center provided sites with templates and access to an engagement coordinator to assist with developing and executing site plans. ResultsCommunity consultation and public disclosure occurred at the coordinating center from February 2021-January 2022 and in the regions of the five additional enrolling sites from September 2023-June 2024. Community consultation included in-person surveys with 789 patients or family members in emergency department or intensive care unit waiting rooms and invitation of more than 200 local groups to town halls or community engagement studios. Public disclosure included (i) social media advertisements viewed more than 1.2 million times, (ii) a trial website with more than 16,000 unique visitors, (iii) informational flyers in hospitals and public settings, and (iv) featured information in traditional media. Completing local community consultation and public disclosure required an average of 139 hours of research personnel time and approximately $18,822 at each site, in addition to coordinating center effort and costs. ConclusionsPre-trial community consultation activities in the RSI trial engaged over 1,000 patients, families, and community members and public disclosure reached over 1.2 million community members. While the total cost and duration of activities at sites were substantially lower than reported in prior EFIC trials, these costs remained significant.

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are increasingly prescribed for weight loss and cardiometabolic health but have been evidenced to lead to loss of lean soft tissue mass. Resistance training (RT) is known to result in increase muscle mass, and indeed preserve muscle mass during weight loss through more traditional weight loss approaches such as energy restriction and bariatric surgery. Yet, its effectiveness in counteracting GLP-1-RA-associated lean soft tissue mass loss remains unclear. This Stage 1 Registered Report outlines a quasi-experimental, retrospective, controlled interrupted time-series analysis using existing data from Kieser Australia members undergoing standardized RT intervention. Participants identified by internal survey to have also been on, or are currently on, GLP-1-RA therapy will be propensity score-matched to controls not receiving the drug. The primary outcome is fat free mass (via bioelectrical impedance analysis), serving as a proxy for lean soft tissue mass. We hypothesize that the effect of RT over time will be non-inferior to the effect of GLP-1-RA, indicating mitigation of lean mass loss. Secondary exploratory outcomes include effects on muscle strength. Simulations regarding estimates of GLP-1-RA treatment use in the Kieser Australia membership suggest we will be able to obtain a sample size of 37 [interquartile range: 8] matched participants per group and that, using additive estimates of the effects of RT and GLP-1-RA treatments from prior meta-analyses suggest adequate we will achieved at least 80% power at an alpha of 0.05 for testing non-inferiority with this sample size. Results will inform clinical strategies to preserve musculoskeletal health during pharmacological weight loss interventions.