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.

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.

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.

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.

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.

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).

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.

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.

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.

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.