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Background: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Methods: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Findings: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p

IMPORTANCE: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. OBJECTIVE: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. DESIGN, SETTING, AND PARTICIPANTS: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. INTERVENTIONS: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. RESULTS: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of −2.0% (1-sided 97.5% CI, −∞ to 1.2%; P

Introduction It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. Methods and analysis An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. Ethics and dissemination This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. Trial registration number ISRCTN11442263.

ObjectivesTo characterise the quality of life, healthcare use and costs associated with early antibiotic treatment of influenza-like illness (ILI) in ‘at-risk’ children.DesignEconomic analysis of a two-arm double-blind parallel group pragmatic randomised controlled trial.SettingChildren were recruited from community-based healthcare settings, including general practices, walk-in centres and hospital ambulatory care.ParticipantsChildren with risk factors for influenza-related complications, including respiratory, cardiac and neurological conditions, who presented within the first 5 days of an ILI.InterventionsCo-amoxiclav 400/57 suspension or placebo.Outcome measuresThis economic analysis focused on quality of life measured by the EQ-5D-Y, symptoms assessed by the Canadian Acute Respiratory Infection and Flu Scale (CARIFS), healthcare use and costs including medication, hospital visits and admissions, general practitioner and nurse contacts. Outcomes were assessed for up to 28 days post randomisation.ResultsInformation on resource use, EQ-5D-Y (day 28) and CARIFS (day 7) was available for 265 (98%), 72 (27%) and 123 (45%) out of 271 participants, respectively. Average costs in the co-amoxiclav group were £25 lower (95% CI −£113 to £65), but this difference was not statistically significant (p=0.566). The difference in EQ-5D-Y scores between groups was also not statistically significant (−0.014 (95% CI −0.124 to 0.096), p=0.798). However, day 7 CARIFS scores were 3.5 points lower in the co-amoxiclav arm (95% CI −6.9 to −0.1, p=0.044).ConclusionsOur findings did not show evidence that early co-amoxiclav treatment improves quality of life or reduces healthcare use and costs in ‘at-risk’ children with ILI, but may reduce symptom severity though confirmation from further research would be important. Reliable data collection from children’s parents/carers was challenging, and resulted in high levels of missing data, which is common in pragmatic trials involving children with acute respiratory tract infections.Trial registration numberISRCTN70714783; EudraCT 2013-002822-21.

Poster presented at ICTMC 2022 Over the past 10 years there has been a significant increase in the number of registered and published pilot cluster-randomised controlled trials (cRCTs). However, there is minimal guidance regarding appropriate sample sizes for pilot cRCTs, despite the fact that pilot studies are often used to estimate parameters for main trials and all pilot trials should justify their choice of sample size. We aimed to conduct an audit of pilot cRCTs from 2010-2020 to document typical sample size for these trials, their justification, and explore trends across time and types of trial. We performed a search of PubMed and Web of Science databases between 2010-2020. The search terms “pilot” or “feasibility” were used, alongside specific terms to identify cRCTs. From included studies we collated key information including planned and actual sample size (number of participants and clusters), number of study arms, whether and how the sample size was justified, and whether an ICC was estimated. To explore differences across trial types we also collected data regarding cluster type, therapeutic area and type of funding. The literature search produced 3168 records of which 178 studies met the inclusion criteria and were analysed. Almost all studies (90%) had two arms, and none had more than four. Most studies were publicly funded (76%), and clusters were predominantly healthcare related (56%), constituting primary care (12%), secondary care (17%) ,social care (16%) and healthcare professionals (11%). We found a median of 4 planned clusters per arm (IQR: 3,6; range: 2,150: ) and median planned participants of 75 per arm (IQR 40,200; range:20,3000 ).Studies randomising education clusters had the largest sample size median of 175 per arm, (IQR 75,305) and those randomising health professionals (median 44 per arm, IQR: 30,96) had the smallest. Most studies did not justify their choice of sample size. Where this was reported, the most common justification was to estimate parameters for a main trial, in order for it to be adequately powered. The majority did not report an ICC estimate: a key parameter for designing a main cRCT. The research suggests that 4 clusters per-arm is the most commonly reported sample size for pilot cRCTs but there was a very wide range. There is little consistency in the justification for the chosen sample size. While most pilot cRCTs are intended to provide estimates of key parameters for a main trial, few reported the ICC, an important parameter in cRCT design. Future work will explore whether and when 4 clusters per-arm is an appropriate sample size.

In recent years, applications of partial randomisation to research funding processes have received growing attention from meta-researchers and research funders (Woods & Wilsdon, 2021a). Partial randomisation, also known as focal randomisation or random selection, is a method for allocating research funding. It is used in addition to peer review, where peer review has reached its limits and the qualities of applications are largely indistinguishable or ‘equally good’ (Bedessem, 2020). In this article we outline essential considerations for any study of partial randomisation of research funding, and consider scenarios in which RCTs would be relevant. We highlight the interdependence of target outcomes, sample availability and statistical power for determining the cost and feasibility of a trial. For many choices of target outcome RCTs may be less practical and more expensive than they first appear (in large part due to issues pertaining to sample size and statistical power). As such, we also introduce and briefly discuss alternatives to RCTs. It is worth noting that many of the considerations relevant to experiments on partial randomisation may also apply to other potential experiments on funding processes (see Bendiscioli et al, 2021).