Utilising primary care electronic health records to deliver the ALABAMA randomised controlled trial of penicillin allergy assessment.

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.

Feasibility and Acceptability Study of a Culturally Adapted Web-Based Intervention to Reduce Suicidal Ideation for Syrian Asylum Seekers and Refugees in the United Kingdom: Protocol for a Mixed Methods Study.

BACKGROUND: The 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. OBJECTIVE: The 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. METHODS: This 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. RESULTS: Recruitment 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. CONCLUSIONS: Despite 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 REGISTRATION: ISRCTN ISRCTN11417025; https://www.isrctn.com/ISRCTN11417025. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56957.

Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial.

Chronic kidney disease (CKD) is associated with a substantial risk of progression to end-stage renal disease and vascular events. The nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone, offers cardiorenal protection for people with CKD and diabetes, but there is uncertainty if the steroidal MRA, spironolactone, provides the same protection. In this prospective, randomized, open, blinded endpoint trial, we assessed the effectiveness of 25 mg spironolactone in addition to usual care or usual care alone for reducing cardiovascular outcomes in stage 3b CKD among an older community cohort (mean age = 74.8 years and s.d. = 8.1). We recruited 1,434 adults from English primary care, of whom 1,372 (96%) were included in the primary analysis. The primary outcome was time from randomization until the first occurrence of death, hospitalization for heart disease, stroke, heart failure, transient ischemic attack or peripheral arterial disease, or first onset of any condition listed not present at baseline. Across 3 years of follow-up, the primary endpoint occurred in 113 of 677 participants randomized to spironolactone (16.7%) and 111 of 695 participants randomized to usual care (16.0%) with no significant difference between groups (hazard ratio = 1.05, 95% confidence interval: 0.81-1.37). Two-thirds of participants randomized to spironolactone stopped treatment within 6 months, predominantly because they met prespecified safety stop criteria. The most common reason for stopping spironolactone was a decrease in the estimated glomerular filtration rate that met prespecified stop criteria (n = 239, 35.4%), followed by participants being withdrawn due to treatment side effects (n = 128, 18.9%) and hyperkalemia (n = 54, 8.0%). In conclusion, we found that spironolactone was frequently discontinued due to safety concerns, with no evidence that it reduced cardiovascular outcomes in people with stage 3b CKD. Spironolactone should not be used for people with stage 3b CKD without another explicit treatment indication. ClinicalTrials.gov registration: ISRCTN44522369 .

Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial.

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

User engagement in clinical trials of digital mental health interventions: a systematic review.

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. DISCUSSION: 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.

Effect of antihypertensive deprescribing on hospitalisation and mortality: long-term follow-up of the OPTiMISE randomised controlled trial.

BACKGROUND: Deprescribing of antihypertensive medications is recommended for some older patients with low blood pressure and frailty. The OPTiMISE trial showed that this deprescribing can be achieved with no differences in blood pressure control at 3 months compared with usual care. We aimed to examine effects of deprescribing on longer-term hospitalisation and mortality. METHODS: This randomised controlled trial enrolled participants from 69 general practices across central and southern England. Participants aged 80 years or older, with systolic blood pressure less than 150 mm Hg and who were receiving two or more antihypertensive medications, were randomly assigned (1:1) to antihypertensive medication reduction (removal of one antihypertensive) or usual care. General practitioners and participants were aware of the treatment allocation following randomisation but individuals responsible for analysing the data were masked to the treatment allocation throughout the study. Participants were followed up via their primary and secondary care electronic health records at least 3 years after randomisation. The primary outcome was time to all-cause hospitalisation or mortality. Intention-to-treat analyses were done using Cox regression modelling. A per-protocol analysis of the primary outcome was also done, excluding participants from the intervention group who did not reduce treatment or who had medication reinstated during the initial trial 12-week follow-up period. This study is registered with the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT2016-004236-38) and the ISRCTN Registry (ISRCTN97503221). FINDINGS: Between March 20, 2017, and Sept 30, 2018, a total of 569 participants were randomly assigned. Of these, 564 (99%; intervention=280; control=284) were followed up for a median of 4·0 years (IQR 3·7-4·3). Participants had a mean age of 84·8 years (SD 3·4) at baseline and 273 (48%) were women. Medication reduction was sustained in 109 participants at follow-up (51% of the 213 participants alive in the intervention group). Participants in the intervention group had a larger reduction in antihypertensives than the control group (adjusted mean difference -0·35 drugs [95% CI -0·52 to -0·18]). Overall, 202 (72%) participants in the intervention group and 218 (77%) participants in the control group experienced hospitalisation or mortality during follow-up (adjusted hazard ratio [aHR] 0·93 [95% CI 0·76 to 1·12]). There was some evidence that the proportion of participants experiencing the primary outcome in the per-protocol population was lower in the intervention group (aHR 0·80 [0·64 to 1·00]). INTERPRETATION: Half of participants sustained medication reduction with no evidence of an increase in all-cause hospitalisation or mortality. These findings suggest that an antihypertensive deprescribing intervention might be safe for people aged 80 years or older with controlled blood pressure taking two or more antihypertensives. FUNDING: British Heart Foundation and National Institute for Health and Care Research.

Nurse-delivered sleep restriction therapy to improve insomnia disorder in primary care: the HABIT RCT.

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 < 0.001, Cohen's d = -0.74), indicating that participants in the sleep restriction therapy arm [mean (standard deviation) Insomnia Severity Index = 10.9 (5.5)] reported lower insomnia severity compared to sleep hygiene [mean (standard deviation) Insomnia Severity Index = 13.9 (5.2)]. Large treatment effects were also found at 3 (d = -0.95) and 12 months (d = -0.72). Superiority of sleep restriction therapy over sleep hygiene was evident at 3, 6 and 12 months for self-reported sleep, mental health-related quality of life, depressive symptoms, work productivity impairment and sleep-related quality of life. Eight participants in each group experienced serious adverse events but none were judged to be related to the intervention. The incremental cost per quality-adjusted life-year gained was £2075.71, giving a 95.3% probability that the intervention is cost-effective at a cost-effectiveness threshold of £20,000. The process evaluation found that sleep restriction therapy was acceptable to both nurses and patients, and delivered with high fidelity. Limitations: While we recruited a clinical sample, 97% were of white ethnic background and 50% had a university degree, which may limit generalisability to the insomnia population in England. Conclusions: Brief nurse-delivered sleep restriction therapy in primary care is clinically effective for insomnia disorder, safe, and likely to be cost-effective. Future work: Future work should examine the place of sleep restriction therapy in the insomnia treatment pathway, assess generalisability across diverse primary care patients with insomnia, and consider additional methods to enhance patient engagement with treatment. Trial registration: This trial is registered as ISRCTN42499563. Funding: The award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/84/01) and is published in full in Health Technology Assessment; Vol. 28, No. 36. See the NIHR Funding and Awards website for further award information.

Insomnia refers to problems with falling asleep or staying asleep, which affects 10% of the adult population. The recommended treatment for insomnia is a psychological treatment called cognitive­behavioural therapy. Research shows this to be a very effective and long-lasting treatment, but there are not enough trained therapists to support the large number of poor sleepers in the United Kingdom. We have developed a brief version of cognitive­behavioural therapy, called sleep restriction therapy, which involves supporting the patient to follow a new sleep­wake pattern. We carried out this study to see if sleep restriction therapy, given by nurses working in general practice, can improve insomnia and quality of life. We searched general practice records and invited people with insomnia to take part. Six hundred and forty-two participants were assigned, by chance, to either sleep restriction therapy or a comparison treatment, called sleep hygiene. Sleep restriction therapy involved meeting with a nurse on four occasions and following a prescribed sleep schedule. Sleep hygiene involved receiving a leaflet of sleep 'do's and dont's'. Those receiving sleep restriction therapy were also provided with the same sleep hygiene leaflet so that the difference between the two groups was whether or not they received nurse treatment. We measured sleep, quality of life, daytime functioning and use of sleep medication through questionnaires, before and after treatment. We calculated the cost to deliver the treatment, as well as the cost of other National Health Service treatments that participants accessed during the study. We also interviewed participants and nurses to understand their views of the treatment. We found that participants in the sleep restriction therapy group experienced greater reduction in their insomnia symptoms compared to sleep hygiene. They also experienced improved sleep, mental health, quality of life and work productivity. The two groups did not differ in their use of prescribed sleep medication. Our results suggest that the treatment is likely to represent good value for money for the National Health Service. Both nurses and participants considered the treatment to be acceptable and beneficial, and they suggested some potential refinements. The study shows that nurse-delivered sleep restriction therapy is likely to be a clinically effective approach to the treatment of insomnia, and good value for money for the National Health Service.

Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited. METHODS: In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600 mg in divided doses on day one, then 800 mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n = 1829), usual care (n = 3256), and other treatments (n = 3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]). INTERPRETATION: In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

FOUND Trial: randomised controlled trial study protocol for case finding of obstructive sleep apnoea in primary care using a novel device.

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.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).

Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients.

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.

Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial.

BACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0·33 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9·20 years (SD 1·79). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0·01, 95% CI -0·15 to 0·17; p<0·0001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.

Cost-utility analysis of molnupiravir for high-risk, community-based adults with COVID-19: an economic evaluation of the PANORAMIC trial.

BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.

Supporting people with type 2 diabetes in effective use of their medicine through mobile health technology integrated with clinical care (SuMMiT-D pilot): results of a feasibility randomised trial.

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.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

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.

Nurse-delivered sleep restriction therapy in primary care for adults with insomnia disorder: a mixed-methods process evaluation.

BACKGROUND: Sleep restriction therapy (SRT) is a behavioural therapy for insomnia. AIM: To conduct a process evaluation of a randomised controlled trial comparing SRT delivered by primary care nurses plus a sleep hygiene booklet with the sleep hygiene booklet only for adults with insomnia disorder. DESIGN AND SETTING: A mixed-methods process evaluation in a general practice setting. METHOD: Semi-structured interviews were conducted in a purposive sample of patients receiving SRT, the practice nurses who delivered the therapy, and also GPs or practice managers at the participating practices. Qualitative data were explored using framework analysis, and integrated with nurse comments and quantitative data, including baseline Insomnia Severity Index score and serial sleep efficiency outcomes to investigate the relationships between these. RESULTS: In total, 16 patients, 13 nurses, six practice managers, and one GP were interviewed. Patients had no previous experience of behavioural therapy, needed flexible appointment times, and preferred face-to-face consultations; nurses felt prepared to deliver SRT, accommodating patient concerns, tailoring therapy, and negotiating sleep timings despite treatment complexity and delays between training and intervention delivery. How the intervention produced change was explored, including patient and nurse interactions and patient responses to SRT. Difficulties maintaining SRT, negative attitudes towards treatment, and low self-efficacy were highlighted. Contextual factors, including freeing GP time, time constraints, and conflicting priorities for nurses, with suggestions for alternative delivery options, were raised. Participants who found SRT a positive process showed improvements in sleep efficiency, whereas those who struggled did not. CONCLUSION: SRT was successfully delivered by practice nurses and was generally well received by patients, despite some difficulties delivering and applying the intervention in practice.

Randomised controlled trial of automated VR therapy to improve positive self-beliefs and psychological well-being in young people diagnosed with psychosis: a study protocol for the Phoenix VR self-confidence therapy trial.

INTRODUCTION: The confidence of young people diagnosed with psychosis is often low. Positive self-beliefs may be few and negative self-beliefs many. A sense of defeat and failure is common. Young people often withdraw from many aspects of everyday life. Psychological well-being is lowered. Psychological techniques can improve self-confidence, but a shortage of therapists means that very few patients ever receive such help. Virtual reality (VR) offers a potential route out of this impasse. By including a virtual coach, treatment can be automated. As such, delivery of effective therapy is no longer reliant on the availability of therapists. With young people with lived experience, we have developed a staff-assisted automated VR therapy to improve positive self-beliefs (Phoenix). The treatment is based on established cognitive behavioural therapy and positive psychology techniques. A case series indicates that this approach may lead to large improvements in positive self-beliefs and psychological well-being. We now aim to conduct the first randomised controlled evaluation of Phoenix VR. METHODS AND ANALYSIS: 80 patients with psychosis, aged between 16 and 30 years old and with low levels of positive self-beliefs, will be recruited from National Health Service (NHS) secondary care services. They will be randomised (1:1) to the Phoenix VR self-confidence therapy added to treatment as usual or treatment as usual. Assessments will be conducted at 0, 6 (post-treatment) and 12 weeks by a researcher blind to allocation. The primary outcome is positive self-beliefs at 6 weeks rated with the Oxford Positive Self Scale. The secondary outcomes are psychiatric symptoms, activity levels and quality of life. All main analyses will be intention to treat. ETHICS AND DISSEMINATION: The trial has received ethical approval from the NHS Health Research Authority (22/LO/0273). A key output will be a high-quality VR treatment for patients to improve self-confidence and psychological well-being. TRIAL REGISTRATION NUMBER: ISRCTN10250113.

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial.

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.

Clinical diagnosis of SARS-CoV-2 infection: An observational study of respiratory tract infection in primary care in the early phase of the pandemic.

BACKGROUND: 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.

Automated virtual reality cognitive therapy versus virtual reality mental relaxation therapy for the treatment of persistent persecutory delusions in patients with psychosis (THRIVE): a parallel-group, single-blind, randomised controlled trial in England with mediation analyses.

BACKGROUND: Persecutory delusions are a major psychiatric problem that often do not respond sufficiently to standard pharmacological or psychological treatments. We developed a new brief automated virtual reality (VR) cognitive treatment that has the potential to be used easily in clinical services. We aimed to compare VR cognitive therapy with an alternative VR therapy (mental relaxation), with an emphasis on understanding potential mechanisms of action. METHODS: THRIVE was a parallel-group, single-blind, randomised controlled trial across four UK National Health Service trusts in England. Participants were included if they were aged 16 years or older, had a persistent (at least 3 months) persecutory delusion held with at least 50% conviction, reported feeling threatened when outside with other people, and had a primary diagnosis from the referring clinical team of a non-affective psychotic disorder. We randomly assigned (1:1) patients to either THRIVE VR cognitive therapy or VR mental relaxation, using a permuted blocks algorithm with randomly varying block size, stratified by severity of delusion. Usual care continued for all participants. Each VR therapy was provided in four sessions over approximately 4 weeks, supported by an assistant psychologist or clinical psychologist. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 2 (therapy mid-point), 4 (primary endpoint, end of treatment), 8, 16, and 24 weeks. The primary outcome was persecutory delusion conviction, assessed by the Psychotic Symptoms Rating Scale (PSYRATS; rated 0-100%). Outcome analyses were done in the intention-to-treat population. We assessed the treatment credibility and expectancy of the interventions and the two mechanisms (defence behaviours and safety beliefs) that the cognitive intervention was designed to target. This trial is prospectively registered with the ISRCTN registry, ISRCTN12497310. FINDINGS: From Sept 21, 2018, to May 13, 2021 (with a pause due to COVID-19 pandemic restrictions from March 16, 2020, to Sept 14, 2020), we recruited 80 participants with persistent persecutory delusions (49 [61%] men, 31 [39%] women, with a mean age of 40 years [SD 13, range 18-73], 64 [80%] White, six [8%] Black, one [1%] Indian, three [4%] Pakistani, and six [8%] other race or ethnicity). We randomly assigned 39 (49%) participants assigned to VR cognitive therapy and 41 (51%) participants to VR mental relaxation. 33 (85%) participants who were assigned to VR cognitive therapy attended all four sessions, and 35 (85%) participants assigned to VR mental relaxation attended all four sessions. We found no significant differences between the two VR interventions in participant ratings of treatment credibility (adjusted mean difference -1·55 [95% CI -3·68 to 0·58]; p=0·15) and outcome expectancy (-0·91 [-3·42 to 1·61]; p=0·47). 77 (96%) participants provided follow-up data at the primary timepoint. Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater improvement in persecutory delusions (adjusted mean difference -2·16 [-12·77 to 8·44]; p=0·69). Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater reduction in use of defence behaviours (adjusted mean difference -0·71 [-4·21 to 2·79]; p=0·69) or a greater increase in belief in safety (-5·89 [-16·83 to 5·05]; p=0·29). There were 17 serious adverse events unrelated to the trial (ten events in seven participants in the VR cognitive therapy group and seven events in five participants in the VR mental relaxation group). INTERPRETATION: The two VR interventions performed similarly, despite the fact that they had been designed to affect different mechanisms. Both interventions had high uptake rates and were associated with large improvements in persecutory delusions but it cannot be determined that the treatments accounted for the change. Immersive technologies hold promise for the treatment of severe mental health problems. However, their use will likely benefit from experimental research on the application of different therapeutic techniques and the effects on a range of potential mechanisms of action. FUNDING: Medical Research Council Developmental Pathway Funding Scheme and National Institute for Health and Care Research Oxford Health Biomedical Research Centre.