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Abstract Background Use of electronic health records (EHR) to provide real-world data for research is established, but using EHR to deliver randomised controlled trials (RCTs) more efficiently is less developed. The Allergy AntiBiotics And Microbial resistAnce (ALABAMA) RCT evaluated a penicillin allergy assessment pathway versus usual clinical care in a UK primary care setting. The aim of this paper is to describe how EHRs were used to facilitate efficient delivery of a large-scale randomised trial of a complex intervention embracing efficient participant identification, supporting minimising GP workload, providing accurate post-intervention EHR updates of allergy status, and facilitating participant follow up and outcome data collection. The generalisability of the EHR approach and health economic implications of EHR in clinical trials will be reported in the main ALABAMA trial cost-effectiveness analysis. Methods A descriptive account of the adaptation of functionality within SystmOne used to deliver/facilitate multiple trial processes from participant identification to outcome data collection. Results An ALABAMA organisation group within SystmOne was established which allowed sharing of trial functions/materials developed centrally by the research team. The ‘ALABAMA unit’ within SystmOne was also created and provided a secure efficient environment to access participants’ EHR data. Processes of referring consented participants, allocating them to a trial arm, and assigning specific functions to the intervention arm were developed by adapting tools such as templates, reports, and protocols which were already available in SystmOne as well as pathways to facilitate allergy de-labelling processes and data retrieval for trial outcome analysis. Conclusions ALABAMA is one of the first RCTs to utilise SystmOne EHR functionality and data across the RCT delivery, demonstrating feasibility and applicability to other primary care RCTs. Trial registration ClinicalTrials.gov: NCT04108637, registered 05/03/2019. ISRCTN: ISRCTN20579216.

Abstract Introduction Digital mental health interventions (DMHIs) overcome traditional barriers enabling wider access to mental health support and allowing individuals to manage their treatment. How individuals engage with DMHIs impacts the intervention effect. This review determined whether the impact of user engagement was assessed in the intervention effect in Randomised Controlled Trials (RCTs) evaluating DMHIs targeting common mental disorders (CMDs). Methods This systematic review was registered on Prospero (CRD42021249503). RCTs published between 01/01/2016 and 17/09/2021 were included if evaluated DMHIs were delivered by app or website; targeted patients with a CMD without non-CMD comorbidities (e.g., diabetes); and were self-guided. Databases searched: Medline; PsycInfo; Embase; and CENTRAL. All data was double extracted. A meta-analysis compared intervention effect estimates when accounting for engagement and when engagement was ignored. Results We identified 184 articles randomising 43,529 participants. Interventions were delivered predominantly via websites (145, 78.8%) and 140 (76.1%) articles reported engagement data. All primary analyses adopted treatment policy strategies, ignoring engagement levels. Only 19 (10.3%) articles provided additional intervention effect estimates accounting for user engagement: 2 (10.5%) conducted a complier-average-causal effect (CACE) analysis (principal stratum strategy) and 17 (89.5%) used a less-preferred per-protocol (PP) population excluding individuals failing to meet engagement criteria (estimand strategies unclear). Meta-analysis for PP estimates, when accounting for user engagement, changed the standardised effect to -0.18 95% CI (-0.32, -0.04) from − 0.14 95% CI (-0.24, -0.03) and sample sizes reduced by 33% decreasing precision, whereas meta-analysis for CACE estimates were − 0.19 95% CI (-0.42, 0.03) from − 0.16 95% CI (-0.38, 0.06) with no sample size decrease and less impact on precision. Discussio n Many articles report user engagement metrics but few assessed the impact on the intervention effect missing opportunities to answer important patient centred questions for how well DMHIs work for engaged users. Defining engagement in this area is complex, more research is needed to obtain ways to categorise this into groups. However, the majority that considered engagement in analysis used approaches most likely to induce bias.

BackgroundThe war in Syria has displaced over 6.8 million people, more than any other conflict since the Second World War. As a result, Syrian asylum seekers and refugees have experienced several life-changing events, resulting in high rates of anxiety, depression, posttraumatic stress disorder, and suicidal ideation (SI). To address the treatment gap and reduce the burden of help-seeking, a web-based intervention to reduce SI developed for general populations was culturally adapted for and with Syrian asylum seekers and refugees in the United Kingdom. The study revealed the importance of understanding their lived experience with migration and the acculturative process in providing treatment for SI. This study will now assess the feasibility and acceptability of the culturally adapted intervention for this population. ObjectiveThe first phase of the study will include recruiting participants and delivering the web-based intervention (1) to assess the feasibility of meeting recruitment goals and recruitment rates and (2) to assess the feasibility of outcome measures. The second phase of the study will include one-to-one semistructured interviews (1) to assess the suitability of the culturally adapted intervention in terms of recruitment and adherence rates and barriers and facilitators to engagement and (2) to assess the acceptability of the intervention in terms of its cultural relevance and appropriateness. MethodsThis is a protocol for a single-group, noncontrolled, mixed methods feasibility and acceptability study of a culturally adapted web-based intervention to reduce SI for Syrian asylum seekers and refugees in the United Kingdom. The study will assess the feasibility of recruitment goals, recruitment rates, adherence rates, and outcome measures using individual participant tracking forms, which will be analyzed quantitatively. The suitability and acceptability of the intervention will be assessed using one-to-one semistructured interviews with 12 participants who completed the intervention, which will be analyzed qualitatively. ResultsRecruitment began in February 2024 and will run until 30 participants are recruited to the study or until the end of July 2024. Thus far, 19 participants have provided informed consent, 16 were eligible and enrolled, and 12 have completed a postintervention interview. No data have been analyzed. The study, including the write-up period, is expected to end in December 2024. ConclusionsDespite experiencing several stressors related to forced displacement and high rates of mental health issues, access to treatment is still limited for Syrian asylum seekers and refugees in the United Kingdom. To address the treatment gap and reduce the burden of help-seeking, a web-based intervention to reduce SI was culturally adapted in collaboration with Syrian asylum seekers and refugees in the United Kingdom. This study will now assess the feasibility and acceptability of the intervention and culturally appropriate recruitment strategies. Trial RegistrationISRCTN ISRCTN11417025; https://www.isrctn.com/ISRCTN11417025 International Registered Report Identifier (IRRID)PRR1-10.2196/56957

Background Insomnia is a prevalent and distressing sleep disorder. Multicomponent cognitive–behavioural therapy is the recommended first-line treatment, but access remains extremely limited, particularly in primary care where insomnia is managed. One principal component of cognitive–behavioural therapy is a behavioural treatment called sleep restriction therapy, which could potentially be delivered as a brief single-component intervention by generalists in primary care. Objectives The primary objective of the Health-professional Administered Brief Insomnia Therapy trial was to establish whether nurse-delivered sleep restriction therapy in primary care improves insomnia relative to sleep hygiene. Secondary objectives were to establish whether nurse-delivered sleep restriction therapy was cost-effective, and to undertake a process evaluation to understand intervention delivery, fidelity and acceptability. Design Pragmatic, multicentre, individually randomised, parallel-group, superiority trial with embedded process evaluation. Setting National Health Service general practice in three regions of England. Participants Adults aged ≥ 18 years with insomnia disorder were randomised using a validated web-based randomisation programme. Interventions Participants in the intervention group were offered a brief four-session nurse-delivered behavioural treatment involving two in-person sessions and two by phone. Participants were supported to follow a prescribed sleep schedule with the aim of restricting and standardising time in bed. Participants were also provided with a sleep hygiene leaflet. The control group received the same sleep hygiene leaflet by e-mail or post. There was no restriction on usual care. Main outcome measures Outcomes were assessed at 3, 6 and 12 months. Participants were included in the primary analysis if they contributed at least one post-randomisation outcome. The primary end point was self-reported insomnia severity with the Insomnia Severity Index at 6 months. Secondary outcomes were health-related and sleep-related quality of life, depressive symptoms, work productivity and activity impairment, self-reported and actigraphy-defined sleep, and hypnotic medication use. Cost-effectiveness was evaluated using the incremental cost per quality-adjusted life-year. For the process evaluation, semistructured interviews were carried out with participants, nurses and practice managers or general practitioners. Due to the nature of the intervention, both participants and nurses were aware of group allocation. Results We recruited 642 participants (n = 321 for sleep restriction therapy; n = 321 for sleep hygiene) between 29 August 2018 and 23 March 2020. Five hundred and eighty participants (90.3%) provided data at a minimum of one follow-up time point; 257 (80.1%) participants in the sleep restriction therapy arm and 291 (90.7%) participants in the sleep hygiene arm provided primary outcome data at 6 months. The estimated adjusted mean difference on the Insomnia Severity Index was −3.05 (95% confidence interval −3.83 to −2.28; p 65 years), sex, baseline insomnia severity [Insomnia Severity Index (ISI) score

Introduction Obstructive sleep apnoea (OSA) is a common, but underdiagnosed, sleep disorder. If untreated, it leads to poor health outcomes, including Alzheimer’s disease, cancer, cardiovascular disease and all-cause mortality. Our aim is to determine the feasibility and cost-effectiveness of moving the testing for OSA into general practice and how general practitioner (GP)-based screening affects overall detection rates.Methods and analysis Randomised controlled trial of case finding of OSA in general practice using a novel Medicines and Healthcare products Regulatory Agency-registered device (AcuPebble SA100) compared with usual care with internal feasibility phase. A diverse sample of general practices (approximately 40) from across the West Midlands Clinical Research Network will identify participants from their records. Eligible participants will be aged 50–70 years with body mass index >30 kg/m2 and diabetes (type 1 or 2) and/or hypertension (office blood pressure >145/90 mm Hg or on treatment). They will exclude individuals with known OSA or chronic obstructive pulmonary disease, or those they deem unable to take part. After eligibility screening, consent and baseline assessment, participants will be randomised to either the intervention or control group. Participants in the intervention arm will receive by post the AcuPebble sleep test kit. Those in the control arm will continue with usual care. Follow-up questionnaires will be completed at 6 months. The study is powered (90%) to detect a 5% difference and will require 606 patients in each arm (713 will be recruited to each arm to allow for attrition). Due to the nature of the intervention, participants and GPs will not be blinded to the allocation.Outcomes Primary: Detection rate of moderate-to-severe OSA in the intervention group versus control group. Secondary: Time to diagnosis and time to treatment for intervention versus control group for mild, moderate and severe OSA; cost-effectiveness analysis comparing the different testing pathways.Ethics and dissemination The trial started on 1 November 2022. Ethical approval was granted from the South Central Oxford A Research Ethics Committee on 9 June 2023 (23/SC/0188) (protocol amendment version 1.3; update with amendment and approval to renumber to V2.0 on 29 August 2023). Patient recruitment began on 7 January 2024; initial planned end date will be on 31 April 2025.Results will be uploaded to the ISRCTN register within 12 months of the end of the trial date, presented at conferences, submitted to peer-reviewed journals and distributed via our patient and public involvement networks.The University of Warwick will act as the trial sponsor. The trial will be conducted in accordance with the Sponsor and Primary Care Clinical Trials Unit standard operating procedures.Trial registration number ISRCTN 16982033.

Abstract Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031

Abstract Background Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. Methods The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. Results Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. Conclusions We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Abstract Background The purpose of this 6-month intervention pilot feasibility randomised trial was to test sending brief messages using mobile phones to promote self-management through taking medication as prescribed to people with type 2 diabetes. This was to inform the design and conduct of a future large-scale United Kingdom-based clinical trial and establish the feasibility of recruitment, the technology used, follow-up, and data collection. Methods A multicentre individually randomised, controlled parallel group trial in primary care, recruiting adults (≥ 35 years) with type 2 diabetes in England. Consenting participants were randomly allocated to receive short message system text messages up to four times a week, or usual care, for a period of 6 months; messages contained behavioural change techniques targeting medication use. The primary outcome was the rate of recruitment to randomisation of participants to the trial with a planned rate of 22 participants randomised per month. The study also aimed to establish the feasibility of follow-up at 6 months, with an aim of retaining more than 80% of participants. Data, including patient-reported measures, were collected at baseline and the end of the 6-month follow-up period, and a notes review was completed at 24 months. Results The trial took place between 26 November 2018 and 30 September 2019. In total 209 participants were randomly allocated to intervention (n = 103) or usual care (n = 106). The maximum rate of monthly recruitment to the trial was 60–80 participants per month. In total, 12,734 messages were sent to participants. Of these messages, 47 were identified as having failed to be sent by the service provider. Participants sent 2,864 messages to the automated messaging system. Baseline data from medical records were available for > 90% of participants with the exception of cholesterol (78.9%). At 6 months, a further HbA1c measurement was reported for 67% of participants. In total medical record data were available at 6 months for 207 (99.0%) of participants and completed self-report data were available for 177 (84.7%) of participants. Conclusion The feasibility of a large-scale randomised evaluation of brief message intervention for people with type 2 diabetes appears to be high using this efficient design. Failure rate of sending messages is low, rapid recruitment was achieved among people with type 2 diabetes, clinical data is available on participants from routine medical records and self-report of economic measures was acceptable. Trial registration ISCTRN ISRCTN13404264. Registered on 10 October 2018.

Background There are data suggesting that intravenous immunoglobulin treatment has some benefit for certain forms of encephalitis but robust evidence from large randomised controlled trials in children with all-cause encephalitis is lacking. Objective To evaluate whether intravenous immunoglobulin treatment improves neurological outcomes in childhood encephalitis when given early in the illness. Design Phase 3b, investigator-initiated, randomised, double-blind, placebo-controlled trial of intravenous immunoglobulin for the treatment of encephalitis in children. Setting Twenty-one NHS Hospitals in the UK. Participants Children aged 6 months to 16 years with a diagnosis of acute or sub-acute encephalitis. Intervention Two doses (1 g/kg/dose) of either intravenous immunoglobulin or matching placebo, given 24–36 hours apart, in addition to standard treatment. Main outcome measure Participants were followed up for 12 months (+/– 4 weeks) after randomisation. The primary outcome measure was a ‘good recovery’ defined as a score of ≤ 2 on the Paediatric Glasgow Outcome Score Extended at 12 months after randomisation. Secondary outcomes The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and intravenous immunoglobulin safety data. Results We planned to recruit 308 children over a 42-month period. After enrolment of 18 participants (8 male; 44%) over 21 months (from December 2015 to September 2017), funding was withdrawn due to slow recruitment and the study was terminated. Ten participants were randomised to the intravenous immunoglobulin group, and eight to the placebo group, and all 18 participants were included in the analysis. At 12 months after randomisation, 9 participants [50%; intravenous immunoglobulin n = 5 (50%), placebo n = 4 (50%)] made good recovery and 5 participants [28%; intravenous immunoglobulin n = 3 (30%), placebo n = 2 (25%)] made a poor recovery. Three participants in the placebo group (43%) experienced a total of 10 serious adverse events compared with none in the intravenous immunoglobulin group but none of the adverse events were judged to be related to the study treatment. No deaths occurred during the study period. Conclusion ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was halted prematurely due to slow recruitment. Given the small sample size, the study was underpowered to evaluate the effect of intravenous immunoglobulin when compared with placebo in childhood encephalitis. The study findings, albeit from a small sample size, support existing evidence that encephalitis results in poor neurological outcomes for many children. Lessons learned from the ImmunoglobuliN in the Treatment of Encephalitis trial would be valuable for the success of future trials set up to address the efficacy of early treatment with intravenous immunoglobulin in all-cause encephalitis in children. Study limitations and future work The study was underpowered to evaluate the efficacy of intravenous immunoglobulin in the treatment of childhood encephalitis due to the small sample size achieved. Future trials should seek to address this important question. Trial registration This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information. Plain language summary Encephalitis (inflammation of the brain) is a serious but rare condition affecting approximately 5 in 100,000 children in England. Encephalitis can have a big impact on affected children and their families. Approximately 12 out of 100 affected children will die and half of those that survive experience varying difficulties in the long term; these might include problems with memory, physical disabilities, seizures and changes in how they think and behave. There is some evidence that a treatment called intravenous immunoglobulin may benefit people affected by encephalitis. Intravenous immunoglobulin contains antibodies obtained from blood donations by different people, which is used to treat some types of inflammation. However, there have been no research studies investigating the effect of intravenous immunoglobulin when used in large numbers of children with all types of encephalitis. Furthermore, although intravenous immunoglobulin is sometimes used to treat children with encephalitis, it is often given after other treatments have been unsuccessful. Outcomes from encephalitis are determined largely by the amount of brain inflammation; it would therefore seem logical that giving a treatment early in the illness to limit the inflammation would be beneficial. In the ImmunoglobuliN in the Treatment of Encephalitis study, we aimed to find out whether giving intravenous immunoglobulin to children with encephalitis early in the illness can help them get better more quickly and reduce the difficulties they experience later on. Half of the children in the trial received intravenous immunoglobulin and the other half received an inactive medicine, known as placebo, in addition to the normal care they would receive in a hospital. We aimed to compare the recovery and outcomes between children in these two groups. This trial was stopped early due to withdrawal of funding, as fewer children than expected were enrolled into the study. Too few children were enrolled for us to be sure whether intravenous immunoglobulin benefits children with encephalitis. However, the trial findings highlight the impact of encephalitis on affected children, with around half of children demonstrating ongoing difficulties 1 year after the illness. Scientific summary Background There is significant mortality and morbidity from encephalitis in children despite the current standard of care. Thus, strategies to improve outcomes in patients with encephalitis are urgently required. Theoretical and empirical evidence suggest a beneficial role of intravenous immunoglobulin (IVIG) for viral and auto-immune forms of encephalitis. Therefore, we set up a prospective randomised controlled trial (RCT) to ascertain the efficacy of early IVIG treatment for all-cause encephalitis in children. In the study, children with encephalitis were randomised to receive two doses of either IVIG or placebo within five working days from the suspicion of an encephalitis diagnosis, in addition to normal standard of care. They were then followed up for 12 months after randomisation. We hypothesised that IVIG could have therapeutic benefit for children with encephalitis when administered early in the illness. Objectives The primary objective was to evaluate the efficacy of early IVIG treatment in childhood encephalitis. This was assessed by comparing the proportion of children in the 2 treatment groups who made good recovery, assessed using the paediatric version of the Glasgow outcome score extended, at 12 months after randomisation. The secondary objectives were to: (1) compare clinical, neurological, neuroimaging and neuropsychological outcomes between the treatment groups, (2) evaluate the proportion of participants with autoimmune encephalitis and (3) confirm the safety of IVIG. Methods Trial design This was a phase 3b multicentre, double-blind, randomised, placebo-controlled trial to evaluate the early use IVIG in childhood encephalitis. Setting Participants were recruited from 21 NHS Hospitals in the UK. Participants Inclusion criteria Participants were eligible if they were aged between 6 weeks and 16 years they met the case definition for possible encephalitis based on the International Encephalitis Consensus parents/guardians provided written informed consent, or assent if appropriate. Exclusion criteria The exclusion criteria included: (1) a high clinical suspicion of bacterial meningitis, (2) prior receipt of IVIG during the admission or known contraindication to IVIG, (3) traumatic brain injury, (4) history of metabolic encephalopathy, stroke, toxic or hypertensive encephalopathy, (5) pre-existing demyelinating disorder, (6) significant renal impairment, (7) hypercoagulable state, (8) hyperprolinaemia, (9) participation in another research trial involving an immunomodulatory treatment, (10) known to be pregnant, (11) any significant disease or clinical research that would impact on participation, or interfere with compliance with study requirements. Randomisation Participants were randomly assigned 1 : 1 ratio to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard care. Randomisation was stratified by age and receipt of steroid treatment. Interventions Two doses of 1 g/kg/dose of either IVIG or a matching volume of placebo were given 24–36 hours apart, with the first dose administered as soon as possible after enrolment and within five working days from the suspicion of an encephalitis diagnosis. The active treatment (IVIG) used in the study was Privigen (100 mg/ml solution), manufactured and provided by CSL Behring. The placebo was a mixture of 0.9% saline + 0.1% human albumin solution, manufactured at the Royal Broadgreen and Liverpool Aseptic Production Unit, Liverpool, UK, under current good manufacturing practice conditions and its Manufacturer’s Importer’s Authorisation licence. The addition of albumin to saline was necessary to make the placebo visually identical to IVIG. Blinding Participants, treating clinicians, parents/guardians and outcome assessors were blinded to the allocated treatment. Primary outcome The primary outcome was good recovery (i.e. score of ≤2) on the paediatric version of the Glasgow Outcome Score-Extended (GOS-E Peds) at 12 months after randomisation. Secondary outcomes Clinical, neurological and neuropsychological outcomes Multiple clinical and neurological measures were collected during the hospital admission, at 4–8 weeks after discharge from acute care, and at 6 and 12 months after randomisation. A blinded neuropsychologist assessment of cognitive function was carried out at 12 months after randomisation. Radiological outcomes Brain magnetic resonance imaging (MRI) findings at 6 months after randomisation were compared with imaging results obtained during the acute illness. Safety data Safety and adverse events (AEs) data were collected until 12 months after randomisation. Identification of immune-mediated encephalitis Presence of specific auto-antibodies in serum was assessed. Statistical methods The analyses were performed on the intention-to-treat population; this included all participants who were randomised, irrespective of study treatment received. In the analysis of the AEs, all participants who received study treatment were included. Since 20% of participants were recruited before the trial was halted, all analyses are descriptive. Results Recruitment took place between 23 December 2015 and 26 September 2017. Recruitment was paused in September 2017 following withdrawal of funding due to slower than anticipated recruitment. Despite strategies implemented to improve recruitment, funding was not reinstated. Attempts at securing alternative funding were unsuccessful; therefore, the trial was closed on 24 October 2017. Participants and demographics At the time of halting the study, 18 participants had been randomised (IVIG n = 10; placebo n = 8). One participant each from the IVIG and placebo groups were withdrawn from the study before receipt of study treatment and one participant in the placebo arm refused a second dose of study treatment. Therefore 16 participants (IVIG n = 9; placebo n = 7) received at least one dose of the study treatment and 15 participants (IVIG n = 9, placebo n = 6) received two full doses of the study treatment. One participant in the placebo group was lost to follow up after the 6 months visit and 1 participant in the IVIG group withdrew consent prior to the visit 12 months after randomisation. The median age at randomisation was 4.09 years [interquartile range (IQR) = 2.0–11.8], 44% were male and 89% were of white ethnicity. Baseline characteristics were well matched across treatment arms. Primary outcome At 12 months after randomisation, 9 participants [50%; IVIG n = 5 (50%); placebo n = 4 (50%)] made a good recovery (score ≤2 on the GOS-E Peds) and 5 participants [28%; IVIG n = 3 (30%), placebo n = 2 (25%)] made a poor recovery (score > 2). Four participants (22%; IVIG n = 2 (20%), placebo n = 2 (25%)] did not undergo a GOS-E Peds assessment at 12 months after randomisation. Secondary outcomes Inpatient data Ten participants [56%; IVIG n = 5 (50%), placebo = 5 (63%)] were admitted to intensive care, and nine of these [90%; IVIG n = 4 (80%), placebo n = 5(100%)] required invasive ventilation, for a median duration of two days (IQR 2.0–3.0). The median length of stay on intensive care was 4.5 days (3.0–6.8) and the overall median length of hospitalisation for acute care was 11 days (7.8–19.5). Epilepsy diagnosis Three participants [17%; IVIG n = 1 (10%), placebo n = 2 (25%)] had a new diagnosis of epilepsy during the study period. Five participants [28%; IVIG n = 2 (20%), placebo n = 3 (38%)] had incomplete data for this outcome. Glasgow Outcome Score-Extended-Peds at 6 months after randomisation Eight participants [44%; IVIG n = 4 (40%), placebo n = 4 (50%)] made a good recovery at 6 months after randomisation, whereas seven participants [39%; IVIG n = 4 (50%), placebo n = 3 (38%)] made a poor recovery. Three participants [17%; IVIG n = 2 (20%), placebo n = 1 (13%)] did not undergo a GOS-E Peds assessment at 6 months after randomisation. Liverpool outcome score At 4–8 weeks after discharge from acute care, 5 participants [28%; IVIG n = 3 (30%), placebo n = 2 (25%)] made a full recovery [defined as a Liverpool Outcome Score (LOS) of >4], whereas 10 participants [56%; IVIG n = 5 (50%), placebo n = 5 (63%)] had minor to severe sequelae. Three participants [17%; IVIG n = 2 (20%); placebo n = 1 (13%)] did not have LOS data collected at this timepoint. At 12 months after randomisation, six participants [33%; IVIG n = 4 (40%), placebo n = 2 (25%)] made full recovery on the LOS assessment, while 8 participants [44%; IVIG n = 4 (40%), placebo n = 4 (50%)] reported minor to severe sequelae. Four participants [22%; IVIG n = 2 (20%); placebo n = 2 (25%)] did not have LOS data collected at this timepoint. Paediatric quality of life assessment Paediatric quality of life scores were available for seven participants [39%; IVIG n = 5 (50%), placebo n = 2 (25%)] at 4–8 weeks after discharge from acute care and for eight participants [44%; IVIG n = 6 (60%), placebo n = 2 (25%)] at 12 months post randomisation. At 4–8 weeks after discharge from acute care, the mean PedsQL score was 77.9 (standard deviation, SD, 11.10) and 56.5 (SD 7.8) for the IVIG and placebo group, respectively. At 12 months, mean PedsQL scores were 79.9 (SD 21.6) and 63.7 (SD 30.1) for the IVIG and placebo groups, respectively. Gross motor function classification system At 4–8 weeks after discharge from acute care, seven participants [39%; IVIG n = 5 (50%); placebo n = 2 (25%)] had mild impairment of gross motor functioning. These data were not available for 11 participants [61%; IVIG n = 5 (50%), placebo n = 6 (75%)] at this timepoint. At 12 months after randomisation, eight participants [44%; IVIG n = 6 (60%); placebo n = 2 (25%)] experienced mild or severe impairment of gross motor function. These data were not available for ten participants [56%; IVIG n = 4 (40%), placebo n = 6 (75%)] at this timepoint. Strengths and difficulties assessment Strengths and Difficulties Questionnaire (SDQ) results were available for seven participants (IVIG n = 5, placebo n = 2) at 4–8 weeks after discharge from acute care and eight participants (IVIG n = 6, placebo n = 2) at 12 months after randomisation. At 4–8 weeks after discharge from acute care, five participants [28%; IVIG n = 4 (40%); placebo n = 1 (13%)] had a close to average SDQ score, one participant [6%, IVIG n = 1 (10%), placebo n = 0] had a slightly raised SDQ score and one participant [6%, IVIG n = 0, placebo n = 1 (13%)] had a very high SDQ score. At 12 months after randomisation, the same number of participants had a close to average score and slightly raised score, but two participants [11%; IVIG n = 1 (10%), placebo n = 1 (13%)] had a very high SDQ score. Adaptive Behaviors Assessment System – second edition At 4–8 weeks after discharge from acute care, five participants [28%; IVIG n = 4 (40%), placebo n = 1 (13%)] had an Adaptive Behaviors Assessment System-second edition (ABAS-II) score that was either similar or higher than the average score of the normative population. At the same time point, three participants [17%; IVIG n = 2 (20%), placebo n = 1 (13%)] had a score that was lower than the average score. Ten participants [56%; IVIG n = 4 (40%), placebo n = 6 (75%)] did not have ABAS-II assessment at this timepoint. At 12 months after randomisation, the same number of participants had a score that was below the average, but four participants [22%; IVIG n = 3 (30%), placebo n = 1 (13%)] had a score that was either similar or higher than the average score, and 11 participants [61%; IVIG n = 5 (50%), placebo n = 6 (75%)] did not have ABAS-II assessment at this timepoint. Neuropsychology assessment Thirteen participants (72%; IVIG n = 8 (80%); placebo n = 5 (63%)] had blinded neuropsychology assessment at 12 months after randomisation; four [30%; IVIG n = 2 (25%), placebo n = 2 (40%)] of these participants were unable to complete the full battery of assessments due to attention or behavioural needs. Five participants [28%; IVIG n = 2 (20%), placebo n = 3 (38%)] did not undergo neuropsychology assessment. Five participants [28%; IVIG n = 4 (40%), placebo n = 1 (13%)] had a score of ≥85 (indicating normal development) for Full-Scale IQ, six [33%; IVIG n = 4 (40%); placebo n = 2 (25%)] for Verbal Comprehension Index (VCI), five [28%; IVIG n = 4 (40%), placebo n = 1 (13%)] for visual spatial; four [22%; IVIG n = 4 (40%), placebo n = 0 (0%)] for working memory index (WMI); and four [22%; IVIG n = 3 (30%); placebo n = 1 (13%)] for Perceptual Reasoning Index (PRI). Two participants (one in each treatment arm) were assessed using the Bayley scale of infant and toddler development, one participant (IVIG arm) had severe neurodevelopmental impairment while the other (placebo arm) had a normal neurodevelopmental outcome. Neuroimaging Nineteen acute neuroimaging scans were available for 13 participants. Five scans (for five unique participants) had abnormal findings; all of these were MRI scans. Four of the abnormal scans showed bilateral lesions. There were nine follow-up scans for eight unique participants of which six scans (for five unique participants) were normal and unchanged from the acute scan. Three follow-up scans (for three unique participants) had abnormal findings; two of these were unchanged from the acute scans and an acute scan was not available for comparison one participant. Autoantibody testing Twelve participants had autoantibody testing. One participant (placebo n = 1) was positive for LGI1 antibodies, and one participant (placebo n = 1) was positive for myelin oligodendrocyte glycoprotein (MOG) antibodies. Two additional participants (IVIG n = 2) were positive for IgG to live neurons, indicating the presence of IgG antibodies binding to neurons, but negative for antibodies to the specific antigens tested for in the study. Safety reporting One participant in the IVIG group reported an AE of special interest; the participant developed a fever during IVIG infusion; however, this was judged to be unrelated to the study treatment. Ten serious AEs occurred in three participants in the placebo group and none in the IVIG group. None of the serious adverse events (SAEs) were judged to be related to the study treatment. No deaths occurred during the study period. Conclusions ImmunoglobuliN in the Treatment of Encephalitis (IgNiTE) was the first RCT to prospectively evaluate the efficacy of IVIG in childhood encephalitis. It was anticipated that data from IgNiTE would provide definitive evidence on which to base the management of children with encephalitis in the UK and worldwide. However, due to slow recruitment, the trial was terminated early. Therefore, the trial did not reach its pre-determined sample size and was underpowered, making it impossible to reach a conclusion on the role of IVIG in treatment of childhood encephalitis. Nonetheless, IgNiTE has highlighted several key learning points. Firstly, IgNiTE has demonstrated the feasibility of setting up a large multi-centre trial efficacy trial in a cohort of children with a rare condition such as encephalitis. Secondly, data from IgNiTE, albeit derived from a small sample size, suggest the safety of IVIG and provide some insight into the burden that encephalitis places on children and the NHS. Over half of the study participants were admitted to the intensive care unit with 90% of those admitted requiring invasive ventilation, with a prolonged overall length of hospitalisation. In addition, a notable proportion of children experienced some degree of disability at follow-up, highlighting the need to prioritise studies aimed at identifying strategies to alleviate the burden from this rare but debilitating disease. For future studies aimed at addressing the efficacy of early IVIG treatment in childhood encephalitis, consideration should be given to practical challenges with setting up RCTs for rare diseases. These include the necessity to recruit from multiple sites to achieve the sample size, the importance of clinical equipoise amongst treating clinicians, and the trade-off between having a stringent but robust set of entry criteria and the impact of this on recruitment. Trial registration This trial is registered as Clinical Trials.gov (NCT02308982) and ISRCTN15791925. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/212/15) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 6. See the NIHR Funding and Awards website for further award information.

Abstract The pediatric population receives the majority of vaccines globally, yet there is a paucity of studies on the transcriptional response induced by immunization in this special population. In this study, we performed a systems-level analysis of immune responses to the trivalent inactivated influenza vaccine adjuvanted with MF-59 in children (15–24 months old) and in young, healthy adults. We analyzed transcriptional responses elicited by vaccination in peripheral blood, as well as cellular and antibody responses following primary and booster vaccinations. Our analysis revealed that primary vaccination induced a persistent transcriptional signature of innate immunity; booster vaccination induced a transcriptional signature of an enhanced memory-like innate response, which was consistent with enhanced activation of myeloid cells assessed by flow cytometry. Furthermore, we identified a transcriptional signature of type 1 interferon response post-booster vaccination and at baseline that was correlated with the local reactogenicity to vaccination and defined an early signature that correlated with the hemagglutinin antibody titers. These results highlight an adaptive behavior of the innate immune system in evoking a memory-like response to secondary vaccination and define molecular correlates of reactogenicity and immunogenicity in infants.

AbstractBackground Early in the COVID-19 pandemic, GPs had to distinguish SARS-CoV-2 from other aetiologies in patients presenting with respiratory tract infection (RTI) symptoms on clinical grounds and adapt management accordingly.Objectives To test the diagnostic accuracy of GPs’ clinical diagnosis of a SARS-CoV-2 infection in a period when COVID-19 was a new disease. To describe GPs’ management of patients presenting with RTI for whom no confirmed diagnosis was available. To investigate associations between patient and clinical features with a SARS-CoV-2 infection.Methods In April 2020–March 2021, 876 patients (9 countries) were recruited when they contacted their GP with symptoms of an RTI of unknown aetiology. A swab was taken at baseline for later analysis. Aetiology (PCR), diagnostic accuracy of GPs’ clinical SARS-CoV-2 diagnosis, and patient management were explored. Factors related to SARS-CoV-2 infection were determined by logistic regression modelling.Results GPs suspected SARS-CoV-2 in 53% of patients whereas 27% of patients tested positive for SARS-CoV-2. True-positive patients (23%) were more intensively managed for follow-up, antiviral prescribing and advice than true-negatives (42%). False negatives (5%) were under-advised, particularly for social distancing and isolation. Older age (OR: 1.02 (1.01–1.03)), male sex (OR: 1.68 (1.16–2.41)), loss of taste/smell (OR: 5.8 (3.7–9)), fever (OR: 1.9 (1.3–2.8)), muscle aches (OR: 2.1 (1.5–3)), and a known risk factor for COVID-19 (travel, health care worker, contact with proven case; OR: 2.7 (1.8–4)) were predictive of SARS-CoV-2 infection. Absence of loss of taste/smell, fever, muscle aches and a known risk factor for COVID-19 correctly excluded SARS-CoV-2 in 92.3% of patients, whereas presence of 3, or 4 of these variables correctly classified SARS-CoV-2 in 57.7% and 87.1%.Conclusion Correct clinical diagnosis of SARS-CoV-2 infection, without POC-testing available, appeared to be complicated.

Objective To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.Design Phase 3b multicentre, double-blind, randomised placebo-controlled trial.Setting Twenty-one hospitals in the UK.Participants Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.Intervention Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.Main outcome measure The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.Secondary outcome measures The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.Results 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.Conclusions The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.Trial registration number Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Introduction Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing.Methods and analysis The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation.Ethics and dissemination This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal.Trial registration ISRCTN20579216.

Abstract Background In the context of COVID-19, NHS Child and Adolescent Mental Health Services (CAMHS) and other children’s mental health services have faced major challenges in providing psychological treatments that (i) work when delivered remotely and (ii) can be delivered efficiently to manage increases in referrals as social distancing measures have been relaxed. Anxiety problems are a common reason for referral to CAMHS, children with pre-existing anxiety problems are particularly vulnerable in the context of COVID-19, and there were concerns about increases in childhood anxiety as schools reopened. The proposed research will evaluate the clinical and cost-effectiveness of a brief online parent-led cognitive behavioural treatment (CBT) delivered by the OSI (Online Support and Intervention for child anxiety) platform with remote support from a CAMHS therapist compared to ‘COVID-19 treatment as usual’ (C-TAU) in CAMHS and other children’s mental health services throughout the COVID-19 pandemic. Methods We will conduct a two-arm, multi-site, randomised controlled non-inferiority trial to evaluate the clinical and cost-effectiveness of OSI with therapist support compared to CAMHS and other child mental health services ‘COVID-19 treatment as usual’ (C-TAU) during the COVID-19 outbreak and to explore parent and therapists’ experiences. Discussion If non-inferiority is shown, the research will provide (1) a solution for efficient psychological treatment for child anxiety disorders while social distancing (for the COVID-19 context and future pandemics); (2) an efficient means of treatment delivery as ‘normal service’ resumes to enable CAMHS to cope with the anticipated increase in referrals; and (3) a demonstration of rapid, high-quality evaluation and application of online interventions within NHS CAMHS to drive forward much-needed further digital innovation and evaluation in CAMHS settings. The primary beneficiaries will be children with anxiety disorders and their families, NHS CAMHS teams, and commissioners who will access a potentially effective, cost-effective, and efficient treatment for child anxiety problems. Trial registration ISRCTN ISRCTN12890382 . Registered prospectively on 23 October 2020.

Introduction There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19.Methods and analysis PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). Eligibility criteria: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18–49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial.Ethics and dissemination Ethical approval granted by South Central–Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals.Trial registration number ISRCTN30448031; EudraCT number: 2021-005748-31.

BackgroundThe conflict in Syria has produced the largest forced displacement crisis since the Second World War. As a result, Syrians have experienced various stressors across the migratory process, putting them at an increased risk of developing mental health issues, including, crucially, suicidal ideation (SI). Despite their high rates of SI across Europe, there remain various barriers to accessing treatment. One way to increase access is the use of culturally adapted digital interventions, which have already shown potential for other minority populations. To culturally adapt the intervention, further research is needed to better understand Syrian asylum seekers’ and refugees’ cultural conceptualizations, coping strategies, and help-seeking behavior for SI. To do so, this study will use a unique cultural adaptation framework to intervene at points of lived experience with the migratory process where Syrian culture and signs of psychopathology converge. Likewise, co-design events will be used to adapt points of experience with the intervention where Syrian culture and the intervention conflict. As the first cultural adaption of a digital SI intervention for Syrian asylum seekers and refugees, this study will hopefully encourage further development of culturally sensitive interventions for the largest refugee population in the United Kingdom and the world. ObjectiveThe objective of the study is to increase access to mental health treatment for Syrian asylum seekers and refugees in the United Kingdom by culturally adapting a digital intervention to reduce SI. MethodsThe study will use experience-based co-design, an action research method, to culturally adapt a digital intervention to reduce SI for Syrian asylum seekers and refugees in the United Kingdom. This will involve conducting 20-30 interviews to understand their lived experiences with the migratory process, cultural conceptualizations of mental health and SI, coping strategies, mental health help-seeking behavior, and perceptions of digital mental health interventions. In addition, 3 co-design events with 6 participants in each will be held to collaboratively adapt the intervention. Touchpoints and themes extracted from each phase will be prioritized by a community panel before adapting the intervention. ResultsThe study began in November 2022 and will continue until the last co-design event in August 2023. The results of the study will then be published by December 2023. ConclusionsAccess to treatment for some of the most severe mental health issues is still limited for Syrian asylum seekers and refugees in the United Kingdom. Cultural adaptations of digital interventions developed for general populations have the potential to increase access to treatment for this population. Specifically, adapting the intervention for Syrian asylum seekers’ and refugees’ experiences with SI in relation to their lived experience with the migratory process may enable greater recruitment and adherence for users of various cultural and ethnic subgroups and levels of SI. International Registered Report Identifier (IRRID)DERR1-10.2196/47627

An estimated 2.7 million people in the UK are potentially prevented from accessing highly effective and inexpensive penicillins as a result of incorrect penicillin allergy records. Removing incorrect penicillin allergy records may lead to improved patient outcomes and contribute to the tackling of antibiotic resistance. We aim to develop and evaluate whether the ‘Penicillin Allergy Assessment Pathway’ (PAAP) is effective in improving patient outcomes. At the first stage of this work, we have focused on understanding patients’ and primary care clinicians’ views of attending and referring to penicillin allergy testing, and then prescribing and consuming penicillin following a negative test result.

Objectives To characterise the quality of life, healthcare use and costs associated with early antibiotic treatment of influenza-like illness (ILI) in ‘at-risk’ children.Design Economic analysis of a two-arm double-blind parallel group pragmatic randomised controlled trial.Setting Children were recruited from community-based healthcare settings, including general practices, walk-in centres and hospital ambulatory care.Participants Children with risk factors for influenza-related complications, including respiratory, cardiac and neurological conditions, who presented within the first 5 days of an ILI.Interventions Co-amoxiclav 400/57 suspension or placebo.Outcome measures This 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.Results Information 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).Conclusions Our 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 number ISRCTN70714783; EudraCT 2013-002822-21.

BackgroundType 2 diabetes is a common lifelong condition that affects over 400 million people worldwide. The use of effective medications and active self-management can reduce the risk of serious complications. However, people often have concerns when starting new medications and face difficulties in taking their medications regularly. Support provided by brief messages delivered through mobile phone–based SMS text messages can be effective in some long-term conditions. We have identified promising behavior change techniques (BCTs) to promote medication adherence in this population via a systematic review and developed SMS text messages that target these BCTs. Feasibility work has shown that these messages have fidelity to intended BCTs, are acceptable to patients, and are successful in changing the intended determinants of medication adherence. We now plan to test this intervention on a larger scale in a clinical trial. ObjectiveThe aim of this trial is to determine the effectiveness and cost-effectiveness of this intervention for reducing cardiovascular risk in people with type 2 diabetes by comparing it with usual care. MethodsThe trial will be a 12-month, multicenter, individually randomized controlled trial in primary care and will recruit adults (aged ≥35 years) with type 2 diabetes in England. Consenting participants will be randomized to receive short SMS text messages intended to affect a change in medication adherence 3 to 4 times per week in addition to usual care. The aim is to test the effectiveness and cost-effectiveness of the intervention when it is added to usual care. The primary clinical outcome will be a composite cardiovascular risk measure. Data including patient-reported measures will be collected at baseline, at 13 and 26 weeks, and at the end of the 12-month follow-up period. With 958 participants (479 in each group), the trial is powered at 92.5% to detect a 4–percentage point difference in cardiovascular risk. The analysis will follow a prespecified plan. A nested quantitative and qualitative process analysis will be used to examine the putative mechanisms of behavior change and wider contextual influences. A health economic analysis will be used to assess the cost-effectiveness of the intervention. ResultsThe trial has completed the recruitment phase and is in the follow-up phase. The publication of results is anticipated in 2024. ConclusionsThis trial will provide evidence regarding the effectiveness and cost-effectiveness of this intervention for people with type 2 diabetes. Trial RegistrationISRCTN Registry ISRCTN15952379; https://www.isrctn.com/ISRCTN15952379 International Registered Report Identifier (IRRID)DERR1-10.2196/32918

Background: Evidence is required to guide the redesign of health care for older people who require hospital admission. Objectives: We assessed the clinical effectiveness and cost-effectiveness of geriatrician-led admission avoidance hospital at home with comprehensive geriatric assessment, the experiences of older people and their caregivers, and how the services differed. Design: A multisite, randomised, open trial of comprehensive geriatric assessment hospital at home, compared with admission to hospital, using a 2 : 1 (hospital at home to hospital) ratio, and a parallel economic and process evaluation. Participants were randomised using a secure online system. Setting: Participants were recruited from primary care or acute hospital assessment units from nine sites across the UK. Participants: Older people who required hospital admission because of an acute change in health. Intervention: Geriatrician-led admission avoidance hospital at home with comprehensive geriatric assessment. Main outcome measures: The main outcome, ‘living at home’ (the inverse of death or living in a residential care setting), was measured at 6-month follow-up. Secondary outcomes at 6 months were the incidence of delirium, mortality, new long-term residential care, cognitive impairment, ability to perform activities of daily living, quality-adjusted survival, length of stay and transfer to hospital. Secondary outcomes at 12 months were living at home, new long-term residential care and mortality. Results: Participants were allocated to hospital at home (n = 700) or to hospital (n = 355). All reported relative risks (RRs) were adjusted and are reported for hospital at home compared with hospital. There were no significant differences between the groups in the proportions of patients ‘living at home’ at 6 months [528/672 (78.6%) vs. 247/328 (75.3%), RR 1.05, 95% confidence interval (CI) 0.95 to 1.15; p = 0.36] or at 12 months [443/670 (66.1%) vs. 219/325 (67.4%), RR 0.99, 95% CI 0.89 to 1.10; p = 0.80]; mortality at 6 months [114/673 (16.9%) vs. 58/328 (17.7%), RR 0.98, 95% CI 0.65 to 1.47; p = 0.92] or at 12 months [188/670 (28.1%) vs. 82/325 (25.2%), RR 1.14, 95% CI 0.80 to 1.62]; the proportion of patients with cognitive impairment [273/407 (67.1%) vs. 115/183 (62.8%), RR 1.06, 95% CI 0.93 to 1.21; p = 0.36]; or in ability to perform the activities of daily living as measured by the Barthel Index (mean difference 0.24, 95% CI –0.33 to 0.80; p = 0.411; hospital at home, n = 521 patients contributed data; hospital, n = 256 patients contributed data) or Comorbidity Index (adjusted mean difference 0.0002, 95% CI –0.15 to 0.15; p = 0.10; hospital at home, n = 474 patients contributed data; hospital, n = 227 patients contributed data) at 6 months. The varying denominator reflects the number of participants who contributed data to the different outcomes. There was a significant reduction in the RR of living in residential care at 6 months [37/646 (5.7%) vs. 27/311 (8.7%), RR 0.58, 95% CI 0.45 to 0.76; p

Summary: Background: The effectiveness of the COVID-19 vaccination programme depends on mass participation: the greater the number of people vaccinated, the less risk to the population. Concise, persuasive messaging is crucial, particularly given substantial levels of vaccine hesitancy in the UK. Our aim was to test which types of written information about COVID-19 vaccination, in addition to a statement of efficacy and safety, might increase vaccine acceptance. Methods: For this single-blind, parallel-group, randomised controlled trial, we aimed to recruit 15 000 adults in the UK, who were quota sampled to be representative. Participants were randomly assigned equally across ten information conditions stratified by level of vaccine acceptance (willing, doubtful, or strongly hesitant). The control information condition comprised the safety and effectiveness statement taken from the UK National Health Service website; the remaining conditions addressed collective benefit, personal benefit, seriousness of the pandemic, and safety concerns. After online provision of vaccination information, participants completed the Oxford COVID-19 Vaccine Hesitancy Scale (outcome measure; score range 7–35) and the Oxford Vaccine Confidence and Complacency Scale (mediation measure). The primary outcome was willingness to be vaccinated. Participants were analysed in the groups they were allocated. p values were adjusted for multiple comparisons. The study was registered with ISRCTN, ISRCTN37254291. Findings: From Jan 19 to Feb 5, 2021, 15 014 adults were recruited. Vaccine hesitancy had reduced from 26·9% the previous year to 16·9%, so recruitment was extended to Feb 18 to recruit 3841 additional vaccine-hesitant adults. 12 463 (66·1%) participants were classified as willing, 2932 (15·6%) as doubtful, and 3460 (18·4%) as strongly hesitant (ie, report that they will avoid being vaccinated for as long as possible or will never get vaccinated). Information conditions did not alter COVID-19 vaccine hesitancy in those willing or doubtful (adjusted p values >0·70). In those strongly hesitant, COVID-19 vaccine hesitancy was reduced, in comparison to the control condition, by personal benefit information (mean difference –1·49, 95% CI –2·16 to –0·82; adjusted p=0·0015), directly addressing safety concerns about speed of development (−0·91, –1·58 to –0·23; adjusted p=0·0261), and a combination of all information (−0·86, –1·53 to –0·18; adjusted p=0·0313). In those strongly hesitant, provision of personal benefit information reduced hesitancy to a greater extent than provision of information on the collective benefit of not personally getting ill (−0·97, 95% CI –1·64 to –0·30; adjusted p=0·0165) or the collective benefit of not transmitting the virus (−1·01, –1·68 to –0·35; adjusted p=0·0150). Ethnicity and gender were found to moderate information condition outcomes. Interpretation: In the approximately 10% of the population who are strongly hesitant about COVID-19 vaccines, provision of information on personal benefit reduces hesitancy to a greater extent than information on collective benefits. Where perception of risk from vaccines is most salient, decision making becomes centred on the personal. As such, messaging that stresses the counterbalancing personal benefits is likely to prove most effective. The messaging from this study could be used in public health communications. Going forwards, the study highlights the need for future health campaigns to engage with the public on the terrain that is most salient to them. Funding: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and NIHR Oxford Health Biomedical Research Centre.

Introduction There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications.Methods and analysis The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50–64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 ‘hot hubs’ and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes.Ethics and dissemination Ethical approval Ref: 20/SC/0158 South Central - Berkshire Research Ethics Committee; IRAS Project ID: 281958; EudraCT Number: 2020-001209-22. Results will be presented to policymakers and at conferences and published in peer-reviewed journals.Trial registration number ISRCTN86534580.

Abstract Background Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.

Abstract Background Persecutory delusions are a major psychiatric problem and are associated with a wide range of adverse outcomes. Our theoretical model views these delusions as unfounded threat beliefs which persist due to defence behaviours (e.g. avoidance) that prevent disconfirmatory evidence being processed. The treatment implications are that patients need to (1) go into feared situations and (2) not use defence behaviours. This enables relearning of safety and hence paranoia diminution. However, this is very difficult for patients due to their severe anxiety. A solution is to use virtual reality (VR) social situations, which are graded in difficulty and which patients find much easier to enter. We have now automated the provision of cognitive therapy within VR using an avatar coach, so that a therapist is not required and the treatment is scalable. In the THRIVE trial, the automated VR cognitive treatment will be tested against a VR control condition. It will contribute to our wider programme of work developing VR for patients with psychosis. Methods Patients with persistent persecutory delusions in the context of non-affective psychosis will be randomised (1:1) to the automated VR cognitive treatment or VR mental relaxation (control condition). Each VR treatment will comprise approximately four sessions of 30 min. Standard care will remain as usual in both groups. Assessments will be carried out at 0, 2, 4 (post treatment), 8, 16, and 24 weeks by a researcher blind to treatment allocation. The primary outcome is degree of conviction in the persecutory delusion (primary endpoint 4 weeks). Effect sizes will be re-established by an interim analysis of 30 patients. If the interim effect size suggests that the treatment is worth pursuing (d > 0.1), then the trial will go on to test 90 patients in total. Secondary outcomes include real world distress, activity levels, suicidal ideation, and quality of life. Mediation will also be tested. All main analyses will follow the intention-to-treat principle. The trial is funded by the Medical Research Council Developmental Pathway Funding Scheme. Discussion The trial will provide the first test of automated cognitive therapy within VR for patients with psychosis. The treatment is potentially highly scalable for treatment services. Trial registration ISRCTN, ISRCTN12497310. Registered on 14 August 2018.

We explore the implications of online social endorsement for the Covid-19 vaccination program in the United Kingdom. Vaccine hesitancy is a long-standing problem, but it has assumed great urgency due to the pandemic. By early 2021, the United Kingdom had the world’s highest Covid-19 mortality per million of population. Our survey of a nationally representative sample of UK adults ( N = 5,114) measured socio-demographics, social and political attitudes, media diet for getting news about Covid-19, and intention to use social media and personal messaging apps to encourage or discourage vaccination against Covid-19. Cluster analysis identified six distinct media diet groups: news avoiders, mainstream/official news samplers, super seekers, omnivores, the social media dependent, and the TV dependent. We assessed whether these media diets, together with key attitudes, including Covid-19 vaccine hesitancy, conspiracy mentality, and the news-finds-me attitude (meaning giving less priority to active monitoring of news and relying more on one’s online networks of friends for information), predict the intention to encourage or discourage vaccination. Overall, super-seeker and omnivorous media diets are more likely than other media diets to be associated with the online encouragement of vaccination. Combinations of (a) news avoidance and high levels of the news-finds-me attitude and (b) social media dependence and high levels of conspiracy mentality are most likely to be associated with online discouragement of vaccination. In the direct statistical model, a TV-dependent media diet is more likely to be associated with online discouragement of vaccination, but the moderation model shows that a TV-dependent diet most strongly attenuates the relationship between vaccine hesitancy and discouraging vaccination. Our findings support public health communication based on four main methods. First, direct contact, through the post, workplace, or community structures, and through phone counseling via local health services, could reach the news avoiders. Second, TV public information advertisements should point to authoritative information sources, such as National Health Service (NHS) and other public health websites, which should then feature clear and simple ways for people to share material among their online social networks. Third, informative social media campaigns will provide super seekers with good resources to share, while also encouraging the social media dependent to browse away from social media platforms and visit reliable and authoritative online sources. Fourth, social media companies should expand and intensify their removal of vaccine disinformation and anti-vax accounts, and such efforts should be monitored by well-resourced, independent organizations.

Objectives To develop a behavioural intervention package to support clinicians and patients to amend incorrect penicillin allergy records in general practice. The intervention aimed to: (1) support clinicians to refer patients for penicillin allergy testing (PAT), (2) support patients to attend for PAT and (3) support clinicians and patients to prescribe or consume penicillin, when indicated, following a negative PAT result.Methods Theory-based, evidence-based and person-based approaches were used in the intervention development. We used evidence from a rapid review, two qualitative studies, and expert consultations with the clinical research team to identify the intervention ‘guiding principles’ and develop an intervention plan. Barriers and facilitators to the target behaviours were mapped to behaviour change theory in order to describe the proposed mechanisms of change. In the final stage, think-aloud interviews were conducted to optimise intervention materials.Results The collated evidence showed that the key barriers to referral of patients by clinicians were limited experience of referral and limited knowledge of referral criteria and PAT. Barriers for patients attending PAT were lack of knowledge of the benefits of testing and lack of motivation to get tested. The key barriers to the prescription and consumption of first-line penicillin following a negative test result were patient and clinician beliefs about the accuracy of PAT and whether taking penicillin was safe. Intervention materials were designed and developed to address these barriers.Conclusions We present a novel behavioural intervention package designed to address the multiple barriers to uptake of PAT in general practice by clinicians and patients. The intervention development details how behaviour change techniques have been incorporated to hypothesise how the intervention is likely to work to help amend incorrect penicillin allergy records. The intervention will go on to be tested in a feasibility trial and randomised controlled trial in England.

IntroductionInsomnia is a prevalent sleep disorder that negatively affects quality of life. Multicomponent cognitive-behavioural therapy (CBT) is the recommended treatment but access remains limited, particularly in primary care. Sleep restriction therapy (SRT) is one of the principal active components of CBT and could be delivered by generalist staff in primary care. The aim of this randomised controlled trial is to establish whether nurse-delivered SRT for insomnia disorder is clinically and cost-effective compared with sleep hygiene advice.Methods and analysisIn the HABIT (Health-professional Administered Brief Insomnia Therapy) trial, 588 participants meeting criteria for insomnia disorder will be recruited from primary care in England and randomised (1:1) to either nurse-delivered SRT (plus sleep hygiene booklet) or sleep hygiene booklet on its own. SRT will be delivered over 4 weekly sessions; total therapy time is approximately 1 hour. Outcomes will be collected at baseline, 3, 6 and 12 months post-randomisation. The primary outcome is self-reported insomnia severity using the Insomnia Severity Index at 6 months. Secondary outcomes include health-related and sleep-related quality of life, depressive symptoms, use of prescribed sleep medication, diary and actigraphy-recorded sleep parameters, and work productivity. Analyses will be intention-to-treat. Moderation and mediation analyses will be conducted and a cost-utility analysis and process evaluation will be performed.Ethics and disseminationEthical approval was granted by the Yorkshire and the Humber - Bradford Leeds Research Ethics Committee (reference: 18/YH/0153). We will publish our primary findings in high-impact, peer-reviewed journals. There will be further outputs in relation to process evaluation and secondary analyses focussed on moderation and mediation. Trial results could make the case for the introduction of nurse-delivered sleep therapy in primary care, increasing access to evidence-based treatment for people with insomnia disorder.Trial registration numberISRCTN42499563

Introduction Self-monitoring of blood pressure (BP) in pregnancy could improve the detection and management of pregnancy hypertension, while also empowering and engaging women in their own care. Two linked trials aim to evaluate whether BP self-monitoring in pregnancy improves the detection of raised BP during higher risk pregnancies (BUMP 1) and whether self-monitoring reduces systolic BP during hypertensive pregnancy (BUMP 2).Methods and analyses Both are multicentre, non-masked, parallel group, randomised controlled trials. Participants will be randomised to self-monitoring with telemonitoring or usual care. BUMP 1 will recruit a minimum of 2262 pregnant women at higher risk of pregnancy hypertension and BUMP 2 will recruit a minimum of 512 pregnant women with either gestational or chronic hypertension. The BUMP 1 primary outcome is the time to the first recording of raised BP by a healthcare professional. The BUMP 2 primary outcome is mean systolic BP between baseline and delivery recorded by healthcare professionals. Other outcomes will include maternal and perinatal outcomes, quality of life and adverse events. An economic evaluation of BP self-monitoring in addition to usual care compared with usual care alone will be assessed across both study populations within trial and with modelling to estimate long-term cost-effectiveness. A linked process evaluation will combine quantitative and qualitative data to examine how BP self-monitoring in pregnancy is implemented and accepted in both daily life and routine clinical practice.Ethics and dissemination The trials have been approved by a Research Ethics Committee (17/WM/0241) and relevant research authorities. They will be published in peer-reviewed journals and presented at national and international conferences. If shown to be effective, BP self-monitoring would be applicable to a large population of pregnant women.Trial registration number NCT03334149

BackgroundResearch funders use a wide variety of application assessment processes yet there is little evidence on their relative advantages and disadvantages. A broad distinction can be made between processes with a single stage assessment of full proposals and those that first invite an outline, with full proposals invited at a second stage only for those which are shortlisted. This paper examines the effects of changing from a one-stage to a two-stage process within the UK's National Institute for Health Research's (NIHR) Research for Patient Benefit (RfPB) Programme which made this change in 2015.MethodsA retrospective comparative design was used to compare eight one-stage funding competitions (912 applications) with eight two-stage funding competitions (1090 applications). Comparisons were made between the number of applications submitted, number of peer and lay reviews required, the duration of the funding round, average external peer review scores, and the total costs involved.ResultsThere was a mean number of 114 applications per funding round for the one-stage process and 136 for the two-stage process. The one-stage process took a mean of 274 days and the two-stage process 348 days to complete, although those who were not funded (i.e. the majority) were informed at a mean of 195 days (mean 79 days earlier) under the two-stage process. The mean peer review score for full applications using the one-stage process was 6.46 and for the two-stage process 6.82 (5.6% difference using a 1-10 scale (with 10 being the highest), but there was no significant difference between the lay reviewer scores. The one-stage process required a mean of 423 peer reviews and 102 lay reviewers and the two-stage process required a mean of 208 peer reviews and 50 lay reviews (mean difference of 215 peer reviews and 52 lay reviews) per funding round. Overall cost per funding round changed from £148,908 for the one-stage process to £105,342 for the two-stage process saving approximately £43,566 per round.ConclusionWe conclude that a two-stage application process increases the number of applications submitted to a funding round, is less burdensome and more efficient for all those involved with the process, is cost effective and has a small increase in peer reviewer scores. For the addition of fewer than 11 weeks to the process substantial efficiencies are gained which benefit funders, applicants and science. Funding agencies should consider adopting a two-stage application assessment process.

Background: Pre-existing T cell responses to influenza have been correlated with improved clinical outcomes in natural history and human challenge studies. We aimed to determine the efficacy, safety and immunogenicity of a T-cell directed vaccine in older people. Methods: This was a multicentre, participant- and safety assessor-blinded, randomised, placebo-controlled trial of the co-administration of Modified Vaccinia Ankara encoding nucleoprotein and matrix protein 1 (MVA-NP+M1) and annual influenza vaccine in participants ≥ 65. The primary outcome was the number of days with moderate or severe influenza-like symptoms (ILS) during the influenza season. Results: 846 of a planned 2030 participants were recruited in the UK prior to, and throughout, the 2017/18 flu season. There was no evidence of a difference in the reported rates of days of moderate or severe ILS during influenza-like illness episodes (unadjusted OR = 0.95, 95% CI: 0.54–1.69; adjusted OR = 0.91, 95% CI: 0.51–1.65). The trial was stopped after one season due to a change in the recommended annual flu vaccine, for which safety of the new combination had not been established. More participants in the MVA-NP+M1 group had transient moderate or severe pain, redness, and systemic responses in the first seven days. Conclusion: The MVA-NP+M1 vaccine is well tolerated in those aged 65 years and over. Larger trials would be needed to determine potential efficacy.

Abstract Background There is concern that existing models of acute hospital care will become unworkable as the health service admits an increasing number of frail older people with complex health needs, and that there is inadequate evidence to guide the planning of acute hospital level services. We aim to evaluate whether geriatrician-led admission avoidance to hospital at home is an effective alternative to hospital admission. Methods/Design We are conducting a multi-site randomised open trial of geriatrician-led admission avoidance hospital at home, compared with admission to hospital. We are recruiting older people with markers of frailty or prior dependence who have been referred to admission avoidance hospital at home for an acute medical event. This includes patients presenting with delirium, functional decline, dependence, falls, immobility or a background of dementia presenting with physical disease. Participants are randomised using a computerised random number generator to geriatrician-led admission avoidance hospital at home or a control group of inpatient admission in a 2:1 ratio in favour of the intervention. The primary endpoint ‘living at home’ (the inverse of death or living in a residential care setting) is measured at 6 months follow-up, and we also collect data on this outcome at 12 months. Secondary outcomes include the incidence of delirium, mortality, new long-term residential care, cognitive impairment, activities of daily living, quality of life and quality-adjusted survival, length of stay, readmission or transfer to hospital. We will conduct a parallel economic evaluation, and a process evaluation that includes an interview study to explore the experiences of patients and carers. Discussion Health systems around the world are examining how to provide acute hospital-level care to older adults in greater numbers with a fixed or shrinking hospital resource. This trial is the first large multi-site randomised trial of geriatrician-led admission avoidance hospital at home, and will provide evidence on alternative models of healthcare for older people who require hospital admission. Trial registration ISRCTN60477865 : Registered on 10 March 2014. Trial Sponsor: University of Oxford. Version 3.1, 14/06/2016.

Introduction Many patients with psychosis experience everyday social situations as anxiety-provoking. The fears can arise, for example, from paranoia, hallucinations, social anxiety or negative-self beliefs. The fears lead patients to withdraw from activities, and this isolation leads to a cycle of worsening physical and mental health. Breaking this cycle requires highly active treatment directly in the troubling situations so that patients learn that they can safely and confidently enter them. However patients with psychosis seldom receive such life-changing interventions. To solve this problem we have developed an automated psychological treatment delivered in virtual reality (VR). It allows patients to experience computer simulations of the situations that they find anxiety-provoking. A virtual coach guides patients, using cognitive techniques, in how to overcome their fears. Patients are willing to enter VR simulations of anxiety-provoking situations because they know the simulations are not real, but the learning made transfers to the real world.Methods and analysis 432 patients with psychosis and anxious avoidance of social situations will be recruited from National Health Service (NHS) secondary care services. In the gameChange trial, they will be randomised (1:1) to the six-session VR cognitive treatment added to treatment as usual or treatment as usual alone. Assessments will be conducted at 0, 6 (post-treatment) and 26 weeks by a researcher blind to allocation. The primary outcome is avoidance and distress in real-life situations, using a behavioural assessment task, at 6 weeks. The secondary outcomes are psychiatric symptoms, activity levels and quality of life. All main analyses will be intention-to-treat. Moderation and mediation will be tested. An economic evaluation will be conducted.Ethics and dissemination The trial has received ethical approval from the NHS South Central - Oxford B Research Ethics Committee (19/SC/0075). A key output will be a high-quality automated VR treatment for patients to overcome anxious avoidance of social situations.Trial registration number ISRCTN17308399.

Background: Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients. Objective: To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma. Design: A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups. Setting: Fourteen hospitals in the UK that manage patients with severe asthma. Participants: Adults (16–75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen. Intervention: Nocturnal, home-based TLA treatment using an Airsonett® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second. Main outcome measures: Primary outcome – frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes – changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness. Results: Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised (n = 119 in the treatment group and n = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9–12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device. Limitations: Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive. Conclusions: Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored. Trial registration: Current Controlled Trials ISRCTN46346208. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 29. See the NIHR Journals Library website for further project information.

Seasonal influenza has a significant annual global impact. Current influenza vaccines work by inducing strain-specific antibodies against the highly polymorphic surface proteins of the influenza virus and need to be redesigned every year, increasing their cost and limiting availability. There is a demand for a more efficacious vaccine, particularly in older adults in which the current vaccines show poor efficacy. The aim is to investigate a novel vaccine, MVA-NP+M1, which targets T cell responses to the nucleoprotein and matrix 1 core proteins of the influenza virus A, which are highly conserved, and therefore may provide long protection against a broad range of influenza strains. INVICTUS is a phase IIb study to determine the safety and efficacy of candidate INfluenza Vaccine MVA-NP+M1 in combination with licensed InaCTivated inflUenza vaccine in adultS aged 65 years and above is a randomised, participant-blinded, placebo-controlled, multi-centre phase IIb efficacy study planned for 2030 volunteers aged 65 and over, in primary care. The primary objective is to assess the efficacy of MVA-NP+M1 co-administered with licensed inactivated quadrivalent influenza vaccine in adults ≥65 years. Participants complete daily diaries to record solicited and unsolicited events in the first four weeks post vaccination, and influenza-like illness (ILI) symptoms and severity throughout the influenza season. We hypothesise an improvement in the primary outcome, a reduction in the average number of days spent with moderate or severe influenza-like illness during periods of influenza circulation, in the group administered with MVA-NP+M1, compared to those in the control group. Registration: ClinicalTrials.gov identifier NCT03300362. Protocol version: INVICTUS Protocol v3.0, 08 June06 2018.

Abstract Background The internet is frequently used to share experiences of health and illness, but this phenomenon has not been harnessed as an intervention to achieve health behaviour change. The aim of this study was to determine the feasibility of a randomised trial assessing the effects of a novel, experience-based website as a smoking cessation intervention. The secondary aim was to measure the potential impact on smoking behaviour of both the intervention and a comparator website. Methods A feasibility randomised controlled single-blind trial assessed a novel, experience-based website containing personal accounts of quitting smoking as a cessation intervention, and a comparator website providing factual information. Feasibility measures including recruitment, and usage of the interventions were recorded, and the following participant-reported outcomes were also measured: Smoking Abstinence Self-Efficacy Questionnaire, the single-item Motivation to Stop Scale, self-reported abstinence, quit attempts and health status outcomes. Eligible smokers from two English regions were entered into the trial and given access to their allocated website for two weeks. Results Eighty-seven smokers were randomised, 65 completed follow-up (75 %). Median usage was 15 min for the intervention, and 5 min for the comparator (range 0.5–213 min). Median logins for both sites was 2 (range 1–20). All participant-reported outcomes were similar between groups. Conclusions It was technically feasible to deliver a novel intervention harnessing the online sharing of personal experiences as a tool for smoking cessation, but recruitment was slow and actual use was relatively low, with attrition from the trial. Future work needs to maximize engagement and to understand how best to assess the value of such interventions in everyday use, rather than as an isolated ‘dose of information’. Trial registration ISRCTN29549695 DOI 10.1186/ISRCTN29549695 . Registered 17/05/2013.

Unnecessary antibiotic prescribing contributes to Antimicrobial Resistance posing a major public health risk. Estimates suggest as many as half of antibiotics prescribed for respiratory infections may be unnecessary. We conducted a three-armed unblinded cluster randomized controlled trial (ISRCTN trial registry 83322985). Interventions were a commitment poster (CP) advocating safe antibiotic prescribing or a CP plus an antimicrobial stewardship message (AM) on telephone appointment booking lines, tested against a usual care control group. The primary outcome measure was antibiotic item dispensing rates per 1000 population adjusted for practice demographics. The outcome measures for post-hoc analysis were dispensing rates of antibiotics usually prescribed for upper respiratory tract infections and broad spectrum antibiotics. In total, 196 practice units were randomized to usual care (n = 60), CP (n = 66), and CP&AM (n = 70). There was no effect on the overall dispensing rates for either interventions compared to usual care (CP 5.673, 95%CI −9.768 to 21.113, p = 0.458; CP&AM, −12.575, 95%CI −30.726 to 5.576, p = 0.167). Secondary analysis, which included pooling the data into one model, showed a significant effect of the AM (−18.444, 95%CI −32.596 to −4.292, p = 0.012). Fewer penicillins and macrolides were prescribed in the CP&AM intervention compared to usual care (−12.996, 95% CI −34.585 to −4.913, p = 0.018). Commitment posters did not reduce antibiotic prescribing. An automated patient antimicrobial stewardship message showed effects and requires further testing.

BACKGROUND:A stepped wedge cluster randomised trial (SWCRT) is a multicentred study which allows an intervention to be rolled out at sites in a random order. Once the intervention is initiated at a site, all participants within that site remain exposed to the intervention for the remainder of the study. The time since the start of the study ("calendar time") may affect outcome measures through underlying time trends or periodicity. The time since the intervention was introduced to a site ("exposure time") may also affect outcomes cumulatively for successful interventions, possibly in addition to a step change when the intervention began. METHODS:Motivated by a SWCRT of self-monitoring for bipolar disorder, we conducted a simulation study to compare model formulations to analyse data from a SWCRT under 36 different scenarios in which time was related to the outcome (improvement in mood score). The aim was to find a model specification that would produce reliable estimates of intervention effects under different scenarios. Nine different formulations of a linear mixed effects model were fitted to these datasets. These models varied in the specification of calendar and exposure times. RESULTS:Modelling the effects of the intervention was best accomplished by including terms for both calendar time and exposure time. Treating time as categorical (a separate parameter for each measurement time-step) achieved the best coverage probabilities and low bias, but at a cost of wider confidence intervals compared to simpler models for those scenarios which were sufficiently modelled by fewer parameters. Treating time as continuous and including a quadratic time term performed similarly well, with slightly larger variations in coverage probability, but narrower confidence intervals and in some cases lower bias. The impact of misspecifying the covariance structure was comparatively small. CONCLUSIONS:We recommend that unless there is a priori information to indicate the form of the relationship between time and outcomes, data from SWCRTs should be analysed with a linear mixed effects model that includes separate categorical terms for calendar time and exposure time. Prespecified sensitivity analyses should consider the different formulations of these time effects in the model, to assess their impact on estimates of intervention effects.

Design and objective This paper describes the protocol for a large-scale pragmatic, randomised controlled trial and economic evaluation to investigate the effectiveness and cost-effectiveness of the self-directed E-Couch social anxiety module versus a waiting list control condition, for reducing sub-clinical social anxiety symptoms in the general population. Study population Community-based adults (aged 18+) with social anxiety symptoms that do not meet the criteria for social anxiety disorder recruited via a direct-to-consumer advertisement on national websites. Intervention and control Intervention is the self-guided E-Couch social anxiety module. Control group participants are placed on a waiting list to receive the intervention at the end of the trial. Both groups receive email and text message reminders. Outcome measures The primary outcome will be change in self-reported social anxiety score using the Social Phobia Inventory (SPIN). Secondary outcomes will be the changes in the following self-report measures: Brief Fear of Negative Evaluation scale (BFNE-S); depression (CES-D); mental wellbeing (SWEMWEBS); health status (SF36); use of health services; safety events; and adherence, retention, and attrition rates. All measures will be administered at baseline, 6 weeks, and 3, 6 and 12 months. Analysis A mixed effects model will be used to analyse the effect of the intervention on the primary and secondary outcomes (intention to treat analysis). Secondary analyses will explore moderators and mediators of effect. A prospective economic evaluation, conducted from a NHS and social care perspective, will provide estimates of cost utility and cost-effectiveness. An interview study will be conducted with 20 participants to explore issues including acceptability, adherence, retention and attrition. Trial registration numbers NCT02451878 and ISRCTN15819951

BACKGROUND:Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. METHODS AND FINDINGS:We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. CONCLUSIONS:Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge. TRIAL REGISTRATION:ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).

Background: Cognitive–behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder. Objectives: This study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated. Design: Participants were randomised to receive (i) child cognitive–behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive–behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother–child interactions (MCIs) (CCBT + MCI). Setting: A NHS university clinic in Berkshire, UK. Participants: Two hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder. Interventions: All families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact. Main outcome measures: Primary clinical outcomes were the child’s primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality-adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost–utility analysis framework with associated uncertainty. Results: MCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62, p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67, p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59, p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53, p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost-effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%. Conclusions: Good outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group. Trial registration: Current Controlled Trials ISRCTN19762288. Funding: This trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (09/800/17) and will be published in full in Health Technology Assessment; Vol. 19, No. 38.

In a previous UK multi-center randomized study 278 children received three doses of 7-valent (PCV-7) or 13-valent (PCV-13) pneumococcal conjugate vaccine at 2, 4 and 12 months of age. At 13 months of age, most of these children had pneumococcal serotype-specific IgG concentrations ≥ 0.35 µg/ml and opsonophagocytic assay (OPA) titers ≥ 8.Children who had participated in the original study were enrolled again at 3.5 years of age. Persistence of immunity following infant immunization with either PCV-7 or PCV-13 and the immune response to a PCV-13 booster at pre-school age were investigated.In total, 108 children were followed-up to the age of 3.5 years and received a PCV-13 booster at this age. At least 76% of children who received PCV-7 or PCV-13 in infancy retained serotype-specific IgG concentrations ≥ 0.35 µg/ml against each of 5/7 shared serotypes. For serotypes 4 and 18C, persistence was lower at 22-42%. At least 71% of PCV-13 group participants had IgG concentrations ≥ 0.35 µg/ml against each of 4/6 of the additional PCV-13 serotypes; for serotypes 1 and 3 this proportion was 45% and 52%. In the PCV-7 group these percentages were significantly lower for serotypes 1, 5 and 7F. A pre-school PCV-13 booster was highly immunogenic and resulted in low rates of local and systemic adverse effects.Despite some decline in antibody from 13 months of age, these data suggest that a majority of pre-school children maintain protective serotype-specific antibody concentrations following conjugate vaccination at 2, 4 and 12 months of age.ClinicalTrials.gov NCT01095471.

Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates.A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined.1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel.The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential.

BackgroundThere have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.Methods and findingsDesignRandomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.SettingOxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.ParticipantsPatients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.InterventionsContinue neuroleptic treatment for 12 mo or switch to an identical placebo.Outcome measuresPrimary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).Results165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) -0.4 (95% confidence interval [CI] -6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) -2.4 (95% CI -8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI >/= 15 benefited on neuropsychiatric symptoms from continuing treatment.ConclusionsFor most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.Trial registrationCochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).

The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies.Controlled-Trials.com ISRCTN 30087513.

Seasonal influenza has a significant annual global impact. Current influenza vaccines work by inducing strain-specific antibodies against the highly polymorphic surface proteins of the influenza virus and need to be redesigned every year, increasing their cost and limiting availability. There is a demand for a more efficacious vaccine, particularly in older adults in which the current vaccines show poor efficacy. The aim is to investigate a novel vaccine, MVA-NP+M1, which targets T cell responses to the nucleoprotein and matrix 1 core proteins of the influenza virus A, which are highly conserved, and therefore may provide long protection against a broad range of influenza strains. INVICTUS is a phase IIb study to determine the safety and efficacy of candidate INfluenza Vaccine MVA-NP+M1 in combination with licensed Ina CTivated infl Uenza vaccine in adult S aged 65 years and above is a randomised, participant-blinded, placebo-controlled, multi-centre phase IIb efficacy study planned for 2030 volunteers aged 65 and over, in primary care. The primary objective is to assess the efficacy of MVA-NP+M1 co-administered with licensed inactivated quadrivalent influenza vaccine in adults ≥65 years. Participants complete daily diaries to record solicited and unsolicited events in the first four weeks post vaccination, and influenza-like illness (ILI) symptoms and severity throughout the influenza season. We hypothesise an improvement in the primary outcome, a reduction in the average number of days spent with moderate or severe influenza-like illness during periods of influenza circulation, in the group administered with MVA-NP+M1, compared to those in the control group. Registration: ClinicalTrials.gov identifier NCT03300362. Protocol version: INVICTUS Protocol v3.0, 08 June06 2018.