BACKGROUND:Nirmatrelvir-ritonavir has been shown to reduce progression to severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unvaccinated high-risk outpatients. The effectiveness of nirmatrelvir-ritonavir in persons who have been vaccinated, infected naturally, or both is unclear. METHODS:In two open-label platform trials (PANORAMIC in the United Kingdom and CanTreatCOVID in Canada), we enrolled higher-risk adults (≥50 years of age or ≥18 years of age with coexisting conditions) in the community who tested positive for SARS-CoV-2 and had been unwell for 5 days or less. The participants were randomly assigned to receive usual care plus nirmatrelvir (300 mg)-ritonavir (100 mg) twice a day for 5 days or to receive usual care alone. The primary outcome was hospitalization or death from any cause within 28 days after randomization. RESULTS:From December 8, 2021, to September 30, 2024, a total of 3516 participants in the PANORAMIC trial and 716 participants in the CanTreatCOVID trial underwent randomization. In the PANORAMIC trial, 14 of 1698 participants (0.8%) in the nirmatrelvir-ritonavir group and 11 of 1673 participants (0.7%) in the usual-care group were hospitalized or died (adjusted odds ratio, 1.18; 95% Bayesian credible interval, 0.55 to 2.62; probability of superiority, 0.334). In the CanTreatCOVID trial, 2 of 343 participants (0.6%) in the nirmatrelvir-ritonavir group and 4 of 324 participants (1.2%) in the usual-care group were hospitalized or died (adjusted odds ratio, 0.48; 95% Bayesian credible interval, 0.08 to 2.23; probability of superiority, 0.830). In a substudy involving 634 participants, viral load was reduced by the end of treatment with nirmatrelvir-ritonavir. Serious adverse events with nirmatrelvir-ritonavir were reported in 9 participants in the PANORAMIC trial and in 4 participants in the CanTreatCOVID trial. CONCLUSIONS:In two open-label trials, nirmatrelvir-ritonavir did not reduce the incidence of hospitalization or death among vaccinated higher-risk participants with SARS-CoV-2 infection. (Funded by the National Institute for Health and Care Research, and others; PANORAMIC ISRCTN number, 2021-005748-31; CanTreatCOVID ClinicalTrials.gov number, NCT05614349.).

BACKGROUND:Sepsis is a common and serious condition, defined as a dysregulated host response to infection, that leads to life-threatening organ dysfunction. In emergency department settings, accurate diagnosis can be challenging, as many non-infectious conditions have similar presenting features and there is no gold standard diagnostic test, which can lead to misdirected use of antibiotics. Procalcitonin is a well characterised biomarker that responds rapidly and with high specificity to the presence of bacterial infection. We aimed to investigate whether supplementing current practice with rapid procalcitonin testing would improve recognition of sepsis and allow reduced antibiotic prescribing with at least no change in overall mortality. METHODS:A parallel, two-arm, open-label, individually randomised controlled trial was done in 20 hospital emergency departments within 17 National Health Service (NHS) Trusts or Health Boards across England and Wales. Patients aged 16 years and older with suspected sepsis were randomly assigned to either usual care or procalcitonin-guided care in a 1:1 ratio via a centrally controlled web-based randomisation programme. Participants, research staff, those assessing outcomes, and statisticians analysing the data were not masked to group assignment. Participants in the usual care group were assessed according to standard clinical management based on National Early Warning Score 2 (NEWS2). In the procalcitonin-guided care group, rapid procalcitonin testing was used in combination with NEWS2 assessment by use of a guidance-only algorithm for clinicians. This algorithm for clinical management was used for both usual care and procalcitonin-guided care groups and clinicians were free to use, ignore, or deviate from the algorithm. The co-primary endpoints were intravenous antibiotic initiation at 3 h (superiority) and 28-day mortality (non-inferiority) from triage assessment, assessed in all randomly assigned consenting participants with data for both co-primary outcomes available. Non-inferiority was concluded for 28-day mortality if the upper bound of the 90% CI was below a 2·5% margin on the risk difference scale. All patients who were randomly assigned to one of the two groups and who consented to data collection at baseline were included in adverse event analysis for the period they were included in the study. The study was registered with ISRCTN (ISRCTN54006056) and is complete. FINDINGS:Between Nov 20, 2020, and Nov 1, 2023, a total of 7667 patients were recruited and randomly assigned to the usual care group (n=3836) or the procalcitonin-guided care group (n=3831). 5453 patients (2748 female, 2703 male, 1 non-binary, 1 data for gender missing) were included in the primary analysis population (2715 usual care, 2738 procalcitonin-guided care). The last 28-day follow-up was on Nov 29, 2023. There was no difference in intravenous antibiotic initiation at 3 h from triage assessment between the two groups: 48·4% (1325/2738 participants) in the procalcitonin-guided care group versus 48·2% (1308/2715 participants) in the usual care group (adjusted risk difference -0·08 percentage points, 95% CI -2·58 to 2·42; p=0·95). Mortality at 28 days was lower in the procalcitonin-guided care group: 13·6% (372/2738 participants) in the procalcitonin-guided care group versus 16·6% (450/2715 participants) in the usual care group (adjusted risk difference -3·12 percentage points, 90% CI -4·68 to -1·57; p=0·0009). The upper bound of the 90% CI was below the non-inferiority margin of 2·5 percentage points and the point of no effect, implying both non-inferiority and superiority at the one-sided 5% level. In the primary analysis population, the procalcitonin test result was considered in clinical decision making in 64·7% (1771/2738) of participants in the procalcitonin-guided care group. Improved mortality was not explained by findings of planned subgroup, sensitivity, or secondary analyses. A total of 180 adverse events were recorded, 53·3% (96 events in 57 [1·9%] of 2968 participants) in the usual care group and 46·7% (84 events in 66 [2·2%] of 3042 participants) in the procalcitonin-guided care group. One (<1%) of 2042 participants in the procalcitonin-guided care group reported a serious adverse event probably or definitely attributable to the procalcitonin test. INTERPRETATION:Making a procalcitonin-guided algorithm available to clinicians in emergency departments did not change intravenous antibiotic initiation at 3 h in patients managed as suspected sepsis, but a decrease in 28-day mortality was seen and further research is needed to understand this finding. FUNDING:National Institute for Health and Care Research.

Background Recent research has concluded that primary care assessment and management of lower urinary tract symptoms (LUTS) requires practical resources. Aim To develop and independently validate risk-prediction models for three common urological conditions based on a combination of simple, minimally invasive index tests in men with LUTS presenting to primary care. Design and setting A prospective, multicentre, diagnostic accuracy study with independent development and validation cohorts set in 67 general practices in England and Wales. Method A total of 601 men presenting to primary care with LUTS, 350 in the development cohort and 251 in the validation cohort, underwent index tests — validated symptom assessment, bladder diary, physical examination, serum prostate specific antigen, uroflowmetry, and post-void residual volume estimation. Invasive urodynamic studies provided a diagnostic reference standard. Risk-prediction models for urodynamic diagnoses were developed and then validated in independent cohorts. Discriminative and calibration performance of the risk-prediction models for diagnosing bladder outlet obstruction (BOO), detrusor underactivity (DU), and detrusor overactivity (DO) using the c-index, calibration slope and plot, and sensitivity and specificity of the models was undertaken. Results The BOO model from the development cohort demonstrated good discriminative performance (optimism-corrected c-index of 0.80). The models derived from the development cohort for DU and DO demonstrated moderate discriminative ability (optimism-corrected c-indices of 0.64 and 0.67, respectively). Similar estimates of c-index were observed for each model within the independent validation cohort (BOO, 0.82; DU, 0.63; and DO, 0.62). Conclusion Using a combination of simple, non-invasive index tests can accurately predict common urological diagnoses in men with LUTS, potentially facilitating earlier initiation of evidence-based treatments and improved management in primary care.

Objectives To assess whether transgender women who have sex with men (TGWSM) sampled in men who have sex with men (MSM) biobehavioural surveys in Ukraine experience different levels of sexual risk, stigma, HIV prevalence and engagement in the HIV care than cisgender MSM (CMSM).Design Analysis of secondary data from three population-level cross-sectional surveys.Setting The analysis was conducted on data from three rounds of integrated biobehavioural surveys of MSM in 27 cities of Ukraine from 2013 to 2018.Participants Data from n=18 621 MSM with n=18 102 CMSM and n=503 TGWSM.Primary and secondary outcome measures The primary outcomes were differences in sexual risk behaviours, HIV testing and treatment uptake, and the secondary outcomes were differences in lifetime experiences of stigma, coercive sex and physical assault (in the 2018 survey only) between CMSM and TGWSM.Results Compared with CMSM, TGWSM were more likely to be clients of non-governmental organisations (adjusted OR, aOR: 1.39, 95% CI 1.15 to 1.67), engage in commercial sex (last month; aOR: 1.28, 95% CI 1.01 to 1.61), have group sex (aOR: 1.31, 95% CI 1.06 to 1.61), more long-term sex partners (last month; adjusted incidence rate ratio: 1.14, 95% CI 1.03 to 1.27), history of imprisonment (aOR: 1.51, 95% CI 1.00 to 2.31) and engage in chemsex (last month, aOR: 1.58, 95% CI 1.12 to 2.23). We found no difference in HIV prevalence (5.17% in TGWSM vs 5.43% in CMSM, p=0.065). In 2018, more TGWSM reported lifetime experience of stigma from family and friends (aOR: 3.58, 95% CI 2.54 to 5.04), general social stigma (aOR: 3.13, 95% CI 2.22 to 4.41), anticipated healthcare stigma (aOR: 3.63, 95% CI 2.53 to 5.16), physical assault (aOR: 2.73, 95% CI 1.85 to 4.03) and coercive sex (aOR: 3.01, 95% CI 1.99 to 4.55) than CMSM.Conclusions TGWSM in Ukraine may be at increased risk of HIV acquisition compared to CMSM due to many factors including elevated levels of stigma and violence. Services specifically tailored for transgender people are needed to help reduce these high-risk behaviours.

Background:Systematic reviews have reported conflicting evidence to confirm if macrolides reduce rates of chronic lung disease of prematurity in at-risk preterm-born infants, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we conducted a double-blind, randomised, placebo-controlled trial to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe chronic lung disease of prematurity in infants born at < 30 weeks' gestation. Methods:Infants recruited from 30 neonatal units (median gestational age 27.0 weeks, interquartile range 25.3-28.6) requiring respiratory support within 72 hours of birth were randomised to intravenous azithromycin 20 mg/kg/day for 3 days followed by 10 mg/kg for 7 days or to placebo. Primary outcome was survival without development of physiologically defined moderate/severe chronic lung disease of prematurity at 36 weeks' postmenstrual age. A total of 796 infants were required to detect 12% improvement in survival without development of moderate or severe chronic lung disease of prematurity, including 10% dropout, with two-sided α-level of 5% and 90% power. The primary outcome was analysed using three-level logistic regression to account for clustering of multiple births and participants within centres and was adjusted for gestational age as a fixed effect. Secondary outcomes included death, chronic lung disease of prematurity severity, treatment interaction with Ureaplasma spp. colonisation, days of invasive and days of non-invasive respiratory support, treatment for nosocomial infections, treated patent ductus arteriosus, severe intraventricular haemorrhage, necrotising enterocolitis, treated retinopathy of prematurity and emergence of azithromycin resistance in stool and respiratory samples. Quantitative polymerase chain reaction identified respiratory Ureaplasma spp. and antibiotic resistance genes. Safety was also monitored. Findings:After three withdrawals, 796 randomised infants were included in the final analyses. Survivors without physiologically defined moderate/severe chronic lung disease of prematurity were: 166/394 (42.1%) and 179/402 (44.5%) in the intervention and placebo groups, respectively (adjusted odds ratio 0.84; 95% confidence interval 0.55 to 1.29; p = 0.43). Secondary outcomes were not significantly different between the treatment groups, except for treated retinopathy of prematurity in survivors (3.5% vs. 7.4%, azithromycin vs. placebo; odds ratio: 0.42, 95% confidence interval 0.18 to 0.98). Ureaplasma spp. colonisation did not influence treatment effect. No significant serious adverse effects were reported. From 1108 (n = 541 azithromycin, n = 567 placebo) respiratory aspirates and 709 stool samples from 348 infants, erm(C) and msr(A) were the most prevalent macrolide-resistance genes, but erm(C) increased with azithromycin treatment in both sample types (11% at baseline, 16% at day 14 in respiratory samples; 0% at baseline, 69% at day 14 in stool samples). Interpretation:Prophylactic use of azithromycin did not improve survival without development of physiologically defined chronic lung disease of prematurity regardless of Ureaplasma spp. colonisation. Thus, it cannot be recommended in clinical practice. Since preterm-born infants are exposed to a range of antibiotics, in addition to the trial azithromycin, judicious use of antibiotics is required, given the emergence of multiresistant bacteria in this vulnerable group of infants. Future work:Follow-up at ages 1 and 2 years will assess the medium-term effects. Investigating whether treatment modulated proinflammatory cytokine concentrations, including whether this was more prevalent in the Ureaplasma spp. colonised or non-colonised group, will be crucial to providing further assurances to the clinical community. Limitations:Limitations include the (limited) missed oxygen reduction tests, inadequate collection of respiratory support data and lower-than-anticipated baseline sampling. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/111/106.

Background:Variation in the way information about potential trial intervention benefits and harms is conveyed within patient information leaflets can cause avoidable information-induced ('nocebo') harm, research waste, and may be unethical. Objectives:1. To develop stakeholder-informed principles to guide how to describe information about potential trial intervention benefits and harms within patient information leaflets. 2. To test whether using these principles are feasible for testing in trials that measure whether they improve recruitment and adverse event rates. 3. To develop and disseminate guidance on how to implement the principles. Methods:We used a mixed methodology consisting of three work packages. Work package 1 involved a modified Delphi survey and consensus meeting to develop the principles for harmonising the way information regarding potential benefits and harms are shared. Work package 2 involved testing whether the principles could be used to transform existing patient information leaflets by recruiting host trials to compare standard patient information leaflets with patient information leaflets developed using the principles 'principled patient information leaflets'. We also set up an infrastructure to test whether they could reduce variation, impact trial recruitment and reduce reported adverse events. Work package 3 involved developing and disseminating guidance for using the principles. Results:For work package 1, 250 participants completed the Delphi survey and 7 principles were agreed upon: (1) all potential intervention harms should be listed, (2) potential harms should be separated into 'serious' and 'less serious', (3) if not all potential harms are known, this needs to be explicitly stated, (4) all potential benefits should be listed, (5) potential benefits and harms associated with trial participation need to be compared with those associated with non-participation, (6) suitable visual representations should be added where appropriate, and (7) information about potential benefits and harms should not be separated by more than one page. For work package 2, we developed principled patient information leaflets for five host trials and interviewed two members of each host trial team. Two host trials agreed to compare the patient information leaflets with principled patient information leaflets using Studies Within a Trial, and we published a protocol for a meta-analysis that will synthesise the results. For work package 3, 25 participants attended a hybrid workshop and recommended that researchers and Research Ethics Committee members should use the principles to design and evaluate patient information leaflets. We produced a guidance booklet and website, which are currently being used by some Health Research Authority Research Ethics Committees. Conclusions:A strong consensus was reached regarding seven principles that can harmonise the way information about the potential benefits and harms of trial interventions is shared. The principles are likely to reduce research waste and avoidable information-induced harm, and may enhance clinical trial ethics. Limitations:Due to COVID-19, the National Institute for Health and Care Research review of ongoing trials that resulted in funding termination for several trials, and highly pressured trial staff with limited capacity to add Studies Within a Trial to their trials, we had to modify our second objective. Whereas we initially intended to actually conduct the Studies Within a Trial, we replaced this with: a protocol for a meta-analysis of Studies Within a Trial, additional research on the need to reduce variation, additional dissemination work, and a paper on the ethical requirement to mention potential benefits and harms of trial interventions in patient information leaflets. Future work:Future work could apply these results to explore how to harmonise the way potential benefits and harms are shared during verbal conversations between researchers and patients during the informed consent process. Funding:This award was funded by the Medical Research Council and the National Institute for Health and Care Research (NIHR) Better Methods, Better Research programme (MRC Award Reference: MR/V020706/1) and is published in full in Health Technology Assessment; Vol. 29, No. 43.

BACKGROUND:Hidradenitis suppurativa (HS) is a long-term skin condition where evidence for management after first-line treatment fails is limited and practice varies across the UK. Medical and surgical treatment options are potential avenues of treatment. Furthermore, patient perspectives on HS treatments have received little attention in research to date. OBJECTIVES:To explore patients' views and experiences of treatment for HS to inform clinical care. METHODS:We conducted a nested qualitative study within a prospective cohort study. Interviews with 35 participants were completed by telephone. Purposive sampling was undertaken. Framework analysis was used to develop themes. RESULTS:Past experiences and knowledge informed patient beliefs and whether an individual felt a treatment option was appropriate or a good 'fit' for them at a specific moment in time. Healthcare professional recommendations can influence a patient's views and which treatment option they ultimately receive. Positive experiences were reported across all treatment types covered in the study. Negative experiences included mediation side-effects, lack of efficacy, delays to procedures and burden of wound care. However, even when personal experiences were not wholly positive for an individual, participants often believed the same treatment may potentially help others with HS, owing to the importance placed on personalization of treatment. CONCLUSIONS:This paper has implications for how healthcare professionals discuss treatment options with people with HS. A 'one-size-fits-all' approach is inappropriate, and shared decision-making that elicits patients' beliefs and preferences is crucial.

The UK government ‘Everyone In’ initiative in response to COVID-19 in England saw an unprecedented number of individuals experiencing homelessness moved into temporary accommodation (TA). A limited supply of settled housing meant swift access to settled accommodation (SA) would not be possible for all. This pilot RCT pursued a unique opportunity to examine the feasibility and acceptability of randomising people experiencing homelessness (PEH) to SA or TA and the impact on COVID-19 infection and housing instability. A pilot RCT, with embedded process and health economic evaluations. 1:1 participant randomisation to SA (intervention group) or TA (control group). Recruitment in two local authorities (LA) in England. Participants were aged 18 and over, in single-person homeless households, temporarily accommodated by the LA with recourse to public funds. Primary outcomes: (i) LA recruitment; (ii) Participant recruitment; (iii) participant retention; (iv) LA adherence. Secondary outcomes: (i) completeness of data collection at 3 and 6 months; (ii) data linkage: percentage of participants consenting to data linkage and successful match rate. Of 144 LAs approached, 26 showed interest in participating, two entered the trial. LA hesitancy to participate reflects an unease with trials in services where RCTs are rare. These recruitment challenges resulted in an amendment from full-scale effectiveness RCT to pilot RCT design. Fifty PEH were recruited (29 ISRCTN69564614 . Registered on December 16, 2020.

Introduction Despite repeated vaccinations against SARS-CoV-2 virus, patients who are immunocompromised remain at very high risk of catching SARS-CoV-2 virus and becoming unwell. AZD7442 (Evusheld) is a long-acting monoclonal antibody treatment that has been shown in clinical trials to prevent SARS-CoV-2 infection for up to a year after a single dose. Vaccines require a healthy immune system to generate protective immunity. AZD7442 may prevent SARS-CoV-2 infection in immunocompromised individuals that may not have responded to repeated vaccinations against SARS-CoV-2 virus. Unlike vaccinations, AZD7442 reaches effective levels within the body a few hours after a single dose. The RAPID-PROTECTION trial will determine the levels of immune protection that AZD7442 offers patients at the very highest risk of SARS-CoV-2 infection and whether this protection can be further enhanced by repeated vaccination against SARS-CoV-2 virus.Methods RAPID-PROTECTION is a multicentre, interventional and open-label adaptive platform trial that aims to recruit 350 immunocompromised participants across five UK centres. Participants will be administered AZD7442 on day 0 followed by a SARS-CoV-2 vaccination 28 days later. Participants will be randomised (1:1) to the Moderna vaccine or Pfizer/BioNTech vaccine. Participant samples will be taken at baseline and at multiple timepoints after the administration of AZD7442.Analysis The participant samples will be analysed to measure the function and magnitude of SARS-CoV-2 specific antibody and T-cell responses at baseline and at multiple timepoints after the administration of AZD7442. The immunological effect of the study interventions will be determined by comparison of the results of immunological assessments at baseline and subsequent timepoints.Ethics and dissemination The trial protocol was approved by the research ethics committee of the National Health Service (reference 22/HRA/0359), Health Research Authority and Health and Care Research Wales on 25 July 2022. Findings will be disseminated through peer-reviewed journals and presented at scientific conferences.Trial registration number ISRCTN53507177.

Trials involving adults who lack capacity to consent can be challenging, partly due to the involvement of ‘proxy’ decision-makers. This is usually a family member, who advises the researchers about the person’s wishes. Families can find decision making difficult and some experience a decisional burden. Following the development of a decision aid for family members making trial participation decisions, we are conducting a mixed-methods randomised Study Within a Trial (SWAT) to evaluate its (cost-)effectiveness. This paper reports the feasibility stage conducted in one host study to inform delivery of the main SWAT. Family members approached to act as a consultee for the host study were randomised 1:1 to receive the decision aid booklet alongside standard study information (intervention), or standard information plus a blank notebook (control), and asked to complete the CONCORD scale (Combined Scale for Proxy Informed Consent Decisions) questions about their experience and take part in a semi-structured interview. Acceptability of the SWAT was assessed through exploring recruitment rates and data completeness, and qualitatively through interviews with family members and research staff. Interviews were analysed using a rapid qualitative approach. In total, 92 family members were randomised to the SWAT and 16 completed the CONCORD questionnaire. Interviews were conducted with consultees (n = 4), and host study staff (n = 3) who also provided resource use data. Differences in time staff spent with consultees were small. Key themes included (1) setting up the SWAT and balancing priorities with the host study, (2) differences when recruiting consultees to a SWAT, (3) feasibility and acceptability of the SWAT, (4) challenges of measuring decision quality and (5) views and experiences of the decision support intervention. The CONSULT SWAT is feasible, but changes to study processes are needed in advance of the main SWAT. The findings suggest that attempting to seamlessly integrate the SWAT into the host study may have inadvertently led to it becoming ‘invisible’ to consultees. The small number of trials involving participants lacking capacity limits opportunities for developing the evidence-base. Recruitment of host trials continues, with a focus on evaluating the intervention in a broad range of populations and settings. The SWAT is registered as SWAT #159 with the Northern Ireland Hub for Trials Methodology Research SWAT repository (registered 09.08.2020).

The TOP-CAT project, part of the HDR UK-funded Transforming Data for Trials programme, aims to develop training resources for trial teams, public partners, and data custodians. This will strengthen capacity to conduct data-enabled trials and embed public perspectives, to support improved access, use, and transparency of health-systems data in research. A purposively-selected group of 22 public contributors and subject matter experts collaborate with the TOP-CAT team on an ongoing basis to co-develop the training resources. These link to the overarching needs of the programme such as a route-map specific for data-enabled trials. Through structured discussions, available literature and resources, training materials are scripted for ‘talking head’ training videos to be made freely available on HDR UK Futures platform. The resources are iteratively refined through public and expert feedback to ensure relevance to trialists' practical needs and to increase public confidence in data-enabled trials. To date in this five-year programme, four modules have been developed alongside more than 10 standalone ‘short’ videos. Public input shaped training content on key aspects of the training modules: Introductory module, resource hub for public contributors, data governance, and data utility. The resources introduce each topic, provide practical guidance, and include case study examples to support trialists. Public contributors emphasised the need for trial teams to understand the implications of data-enabled methods and prioritise transparency in their work. While developed for trialists, the materials also offer valuable guidance for all researchers working with administrative and health data, particularly governance and data utility considerations. By integrating public perspectives, the training enhances trialists’ confidence in navigating complex data environments while fostering trust and accountability in research. Embedding public perspectives in capacity-building initiatives ensures researchers are equipped to conduct data-enabled trials responsibly. The co-produced resources strengthen governance, transparency, and public trust while offering broader applicability beyond trials. Ongoing collaboration will ensure training remains relevant as the use of health and administrative data in research continues to evolve.

Background Procalcitonin is a rapid response biomarker specific for bacterial infection, which is not routinely used in the UK National Health Service. We aimed to assess whether using a procalcitonin-guided algorithm would safely reduce the duration of antibiotic therapy compared with usual care, in which C-reactive protein is the commonly used biomarker. Methods The BATCH trial was a pragmatic, multicentre, open-label, parallel, two-arm, individually randomised, controlled trial conducted in 15 hospitals in England and Wales. Children aged 72 h to 18 years who were admitted to hospital and were being treated with intravenous antibiotics for suspected or confirmed bacterial infection and who were expected to remain on intravenous antibiotics for more than 48 h were enrolled. Participants were randomly assigned (1:1) to receive either current clinical management alone (usual care group) or clinical management with the addition of a procalcitonin test guided algorithm (procalcitonin group). Participants were randomly assigned by minimisation, with site and age group (0-6 months, 6 months to 2 years, 2-5 years, and older than 5 years) as minimisation factors and a random element to reduce predictability. Participants were randomly assigned remotely using a secure 24 h web-based randomisation programme. The coprimary outcomes were duration of intravenous antibiotic use, assessed for superiority, and a composite safety measure, assessed for non-inferiority (non-inferiority margin 5%). The primary analysis sample for each coprimary endpoint included all randomly assigned participants with available outcome data. This trial is registered with the International Standard Randomised Controlled Trial Number registry, ISRCTN11369832. Findings Between June 11, 2018, and Oct 12, 2022, 15 282 children were screened for eligibility, 1949 of whom were randomly assigned to receive procalcitonin-guided antibiotic therapy (n=977) or usual care (n=972). The median intravenous antibiotic duration was 960 h (IQR 595-1555) in the procalcitonin group and 997 h (612-1538) in the usual care group (hazard ratio 096 [95% CI 087-105]). 78 (9%) of 917 participants in the procalcitonin group and 85 (9%) of 904 participants in the usual care group had at least one event covered by the composite safety outcome measure (estimated adjusted risk difference -081% [95% CI upper bound 111]). Interpretation In children with suspected or confirmed bacterial infection admitted to hospitals in England and Wales for intravenous antibiotic treatment of at least 48 h, the introduction of a procalcitonin-guided algorithm did not reduce duration of intravenous antibiotics treatment and is non-inferior to usual care for safety outcomes. Therefore, evidence does not support the use of procalcitonin-guided algorithms where robust effective paediatric antibiotic stewardship programmes are established.

BACKGROUND/AIMS:Existing regulatory and ethical guidance does not address real-life complexities in how clinical trial participants' level of participation may change. If these complexities are inappropriately managed, there may be negative consequences for trial participants and the integrity of trials they participate in. These concerns have been highlighted over many years, but there remains no single, comprehensive guidance for managing participation changes in ways that address real-life complexities while maximally promoting participant interests and trial integrity. Motivated by the lack of agreed standards, and observed variability in practice, representatives from academic clinical trials units and linked organisations in the United Kingdom initiated the PeRSEVERE project (PRincipleS for handling end-of-participation EVEnts in clinical trials REsearch) to agree on guiding principles and explore how these principles should be implemented. METHODS:We developed the PeRSEVERE principles through discussion and debate within a large, multidisciplinary collaboration, including research professionals and public contributors. We took an inclusive approach to drafting the principles, incorporating new ideas if they were within project scope. Our draft principles were scrutinised through an international consultation survey which focussed on the principles' clarity, feasibility, novelty and acceptability. Survey responses were analysed descriptively (for category questions) and using a combination of deductive and inductive analysis (for open questions). We used predefined rules to guide feedback handling. After finalising the principles, we developed accompanying implementation guidance from several sources. RESULTS:In total, 280 people from 9 countries took part in the consultation survey. Feedback showed strong support for the principles with 96% of respondents agreeing with the principles' key messages. Based on our predefined rules, it was not necessary to amend our draft principles, but comments were nonetheless used to enhance the final project outputs. Our 17 finalised principles comprise 7 fundamental, 'overarching' principles, 6 about trial design and setup, 2 covering data collection and monitoring, and 2 on trial analysis and reporting. CONCLUSION:We devised a comprehensive set of guiding principles, with detailed practical recommendations, to aid the management of clinical trial participation changes, building on existing ethical and regulatory texts. Our outputs reflect the contributions of a substantial number of individuals, including public contributors and research professionals with various specialisms. This lends weight to our recommendations, which have implications for everyone who designs, funds, conducts, oversees or participates in trials. We suggest our principles could lead to improved standards in clinical trials and better experiences for participants. We encourage others to build on our work to explore the application of these ideas in other settings and to generate empirical evidence to support best practice in this area.

INTRODUCTION:HIV prevention methods, such as pre-exposure prophylaxis (PrEP), have been a significant contributing factor to a global decline in HIV transmission. PrEP has been available through the NHS in Wales since 2017. However, access is exclusively via sexual health clinics, and those accessing PrEP do not reflect those being diagnosed with HIV. Widening access beyond sexual health clinics may be one approach to encourage more equitable uptake, and there is growing interest in offering PrEP services in community pharmacies. We, therefore, aimed to explore the acceptability of PrEP services being delivered through community pharmacies among prospective service users. METHODS:We conducted a qualitative interview study of people living in Wales who either (i) currently access, (ii) previously accessed or are (iii) considering accessing PrEP via a sexual health clinic. Participants were recruited via community networks, and interviews were conducted virtually. Our topic guide was informed by Levesque's conceptual framework of access to healthcare, and we used reflexive thematic analysis. RESULTS:We interviewed 24 participants and included data from 20 in the analysis. Four themes were generated: experiences of accessing PrEP via sexual health clinics, the prospect of PrEP access via community pharmacies, other community settings in which PrEP may be accessed and concerns around integrated healthcare and healthcare data. CONCLUSION:PrEP access via community pharmacy is likely to be an acceptable option for people. There are uncertainties surrounding what a PrEP service would look like in a community pharmacy setting, and this would need clarifying to prospective users to increase the salience of access. PATIENT AND PUBLIC CONTRIBUTION:A team-based approach was taken for developing the topic guide and agreeing on the codes for this study. This included people with lived experience of accessing PrEP in Wales.

Clinical trial participants must understand the possible risks and benefits of trial interventions before providing their informed consent to participate. The aim of this commentary is twofold: to summarize the discrepancies in the extent to which patient information leaflets (PILs) list potential benefits and harms of trial interventions; and to highlight subsequent ethical issues that may result from failure to disclose potential benefits or harms . A review of 247 patient information leaflets (PILs) found that the extent to which potential benefits and harms are described varies, with 28 (11

Lower urinary tract symptoms particularly affect older men and their quality of life. General practitioners currently have no easily available assessment tools to diagnose lower urinary tract symptom causes. Referrals to urology specialists are increasing. General practitioner access to simple, accurate tests and clinical decision tools could facilitate management of lower urinary tract symptoms in primary care. To determine which of several index tests in combination, best predicted three diagnoses (detrusor overactivity, bladder outlet obstruction and/or detrusor underactivity) in men presenting with lower urinary tract symptoms in primary care. To develop and validate three diagnostic prediction models, and a prototype primary care clinical decision support tool. Prospective diagnostic accuracy study. Two participant cohorts, for development and validation, underwent simple index tests and a reference standard (invasive urodynamics). General practices in England and Wales. Men (16 years and over) consulting their general practitioner with lower urinary tract symptoms. Separate calculations for model development and validation cohorts, from literature estimates of detrusor overactivity, bladder outlet obstruction and detrusor underactivity prevalences of 57%, 31% and 16%, respectively. Twelve potential predictors considered for three diagnostic models. The primary outcome was diagnostic model sensitivity and specificity for detecting bladder outlet obstruction, detrusor underactivity and detrusor overactivity, with 75.0% considered minimum clinically useful performance. Three separate logistic regression models generated with index test variables to predict the presence of bladder outlet obstruction, detrusor overactivity, detrusor underactivity conditions in men with lower urinary tract symptoms. One model each was developed and validated for bladder outlet obstruction and detrusor underactivity, two for detrusor overactivity (detrusor overactivity main, detrusor overactivity sensitivity analysis 2). Age, voiding symptoms subscore, prostate-specific antigen level, median maximum flow rate, median voided volume were predictors for bladder outlet obstruction. Median maximum flow rate and post-void residual volume were predictors for detrusor underactivity. Age, post-void residual volume and median voided volume were included in detrusor overactivity main model, while age and storage symptoms subscore predicted detrusor overactivity sensitivity analysis 2. For all four models, sensitivity of 75.0% could be achieved with a specificity of 74.2%, 47.3%, 45.6% and 46.2% for bladder outlet obstruction, detrusor underactivity, detrusor overactivity main and detrusor overactivity sensitivity analysis 2 models, respectively. Similarly, a specificity of 75.0% could be achieved with a sensitivity of 71.3%, 39.8%, 33.3% and 62.7% for bladder outlet obstruction, detrusor underactivity, detrusor overactivity main and detrusor overactivity sensitivity analysis 2 models, respectively. The prototype tool (not yet intended for use in practice) is available at Primary care Management of lower Urinary tract Symptoms decision aid for lower urinary tract symptoms (shinyapps.io). General practitioner feedback during tool development and small-scale user-testing in simulated consultation scenarios was favourable. Patients supported such management in primary care. This was a prospective, multicentre study in an appropriate primary care population. Most of the index tests are possible routinely in primary care or at home by patients. The diagnostic models were validated in a separate cohort from the same population. Limitations include that target condition prevalences may differ in other populations. We identified sensitivities and specificities of diagnostic models for detrusor overactivity, bladder outlet obstruction and detrusor underactivity in routine United Kingdom practice and developed a prototype clinical decision support tool. Economic modelling, a feasibility trial and powered randomised controlled trial are needed to evaluate the Primary care Management of lower Urinary tract Symptoms tool in practice. Current Controlled Trials ISRCTN10327305. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/40/05) and is published in full in Health Technology Assessment; Vol. 29, No. 1. See the NIHR Funding and Awards website for further award information.

Objectives The aim of the scoping review was to identify the existing literature on public and professional’s perspectives about inclusivity and diversity in trials that use routinely collected data. The review will inform the development of training for researchers to promote best practice for inclusive trial design. Methods The scoping review followed the 6-stage Arksey and O'Malley methodology framework, involving a systematic search of relevant databases and selection of publications based on predefined criteria. Those included were collated, summarised and reported using a thematic approach. The review included international publications to ensure a global perspective. The findings have been discussed in consultation with the HDR UK-funded Transforming Data for Trials’ public advisory group and key messages have been embedded into a training module to ensure its relevance and applicability. This module specifically focusses on equity insights for those that work on trials that use health systems data (HSD). Results We will present the results of the scoping review, including how the use of HSD can enhance inclusive trial design and areas where it does not. Preliminary results from 47 publications to date indicate a range of views from under-served groups toward the use of this data in trials from both public and professional opinion. The review has also identified data-enabled strategies and challenges related to inclusivity and diversity in trials. A training module is in development to begin to address these challenges, providing practical guidance and resources to enhance trialist’s best practice knowledge around inclusive trial design using HSD. The public voice is represented in the interpretation of the scoping review findings and content of the training, including key quotes and discussions from workshops. Conclusion This work explores ways to make trials more inclusive and diverse when using HSD and will contribute to building capacity in the field of real-world data research. The training will offer valuable insights into different research partners perspectives, guiding future inclusive trials and training initiatives.

BACKGROUND:No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. METHODS:This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation. FINDINGS:Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. INTERPRETATION:In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat. FUNDING:UK Research and Innovation and National Institute for Health and Care Research.

BackgroundClinical trials are fundamental to healthcare, however, they also contribute to anthropogenic climate change. Following previous work to develop and test a method and guidance to calculate the carbon footprint of clinical trials, we have now applied the guidance to 10 further UK and international, academically sponsored clinical trials to continue the identification of hotspots and opportunities for lower carbon trial design.Methods10 collaborating clinical trial units (CTUs) self-identified and a trial was selected from their portfolio to represent a variety of designs, health areas and interventions. Trial activity data was collated by trial teams across 10 modules spanning trial setup through to closure, then multiplied by emission factors provided in the guidance to calculate the carbon footprint. Feedback was collected from trial teams on the process, experience and ease of use of the guidance.ResultsWe footprinted 10 trials: 6 investigational medicinal product trials, 1 nutritional, 1 surgical, 1 health surveillance and one complex intervention trial. Six of these were completed and four ongoing (two in follow-up and two recruiting). The carbon footprint of the 10 trials ranged from 16 to 765 tonnes CO2e. Common hotspots were identified as CTU emissions, trial-specific patient assessments and trial team meetings and travel. Hotspots for specific trial designs were also identified. The time taken to collate activity data and complete carbon calculations ranged from 5 to 60 hours. The draft guidance was updated to include new activities identified from the 10 trials and in response to user feedback.DiscussionThere are opportunities to reduce the impact of trials across all modules, particularly trial-specific meetings and travel, patient assessments and laboratory practice. A trial’s carbon footprint should be considered at the design stage, but work is required to make this common place.

ABSTRACTIntroductionThe impact of multiple health conditions on bowel cancer screening is currently unknown. We explored the impact of multiple health conditions on bowel cancer screening perceptions, experience and clinical management decisions following a positive stool test.MethodsSemi‐structured qualitative interviews were conducted remotely with Bowel Screening Wales staff (n = 16) stratified by regional location and role and with screening participants (n = 19) stratified by age, gender and comorbidity. Interview topics were guided by the Common‐Sense Model.ResultsScreening participants, regardless of comorbidity status, placed great emphasis on the importance of early detection of cancer and completing the bowel screening process. Screening staff emphasised comorbidities in the clinical decision‐making process; however, screening participants had low awareness of the impact that comorbidities can have on bowel screening. Participants describe how the presence of multiple health conditions can mask potential bowel symptoms and influence beliefs about follow‐up.ConclusionBowel screening staff try to individualise the service to meet participant needs. The potential mismatch in screening staff and participant awareness and expectations of the bowel screening and diagnostic process needs to be addressed. Clearer and more regular communication with screening participants could support the screening process, particularly for those with significant coexisting health conditions or facing time delays. The possible masking effects and misattribution of symptoms because of comorbidities highlight an opportunity for education and raising awareness for screening participants and a potential area of focus for discussions in clinical consultations and staff training.Patient and Public ContributionProject funding included costs for patients and public contributors to be compensated for their contributions to the project, in line with current standards. A patient and public contributor was involved in the design of the study, including protocol development, and the interpretation of key findings and implications for patients, which are subsequently reflected within the manuscript.