Cutting through the noise during crisis by enhancing the relevance of research to policymakers

Background:It is widely recognised that policymakers use research deemed relevant, yet little is understood about ways to enhance perceived relevance of research evidence. Observing policymakers' access of research online provides a pragmatic way to investigate predictors of relevance.Aims and objectives:This study investigates a range of relevance indicators including committee assignments, public statements, issue prevalence, or the policymaker's name or district.Methods:In a series of four rapid-cycle randomised control trials (RCTs), the present work systematically explores science communication strategies by studying indicators of perceived relevance. State legislators, state staffers, and federal staffers were emailed fact sheets on issues of COVID (Trial 1, N = 3403), exploitation (Trial 2, N = 6846), police violence (Trial 3, N = 3488), and domestic violence (Trial 4, N = 3888).Findings:Across these trials, personalising the subject line to the legislator's name or district and targeting recipients based on committee assignment consistently improved engagement. Mentions of subject matter in public statements was inconsistently associated, and state-level prevalence of the issue was largely not associated with email engagement behaviour.Discussion and conclusions:Together, these results indicate a benefit of targeting legislators based on committee assignments and of personalising the subject line with legislator information. This work further operationalises practical indicators of personal relevance and demonstrates a novel method of how to test science communication strategies among policymakers. Building enduring capacity for testing science communication will improve tactics to cut through the noise during times of political crisis.

Biomarker-guided duration of antibiotic treatment in children hospitalised with confirmed or suspected bacterial infection: statistical analysis plan for the BATCH trial and PRECISE sub-study.

INTRODUCTION: The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. METHODS: The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. RESULTS: Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. CONCLUSION: We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. TRIAL REGISTRATION: BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.

The effect of TRV027 on coagulation in COVID 19: A pilot randomized, placebo-controlled controlled trial.

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear, one hypothesis is that loss of Angiotensin Converting Enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double blind randomised, placebo controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19 (REC ref. 20/HRA/3414), Clinical Trial No. NCT04419610. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group, however, this did not reach statistical significance (p=0.15). A Bayesian analysis demonstrated there was a 92% probability that this change represented a true drug effect.

Statistical analysis plan for HOMESIDE: a randomised controlled trial for home-based family caregiver-delivered music and reading interventions for people living with dementia.

BACKGROUND: Most people with dementia live in the community, not in residential care. Therefore, quality informal care for them is critical for managing behavioural and psychological symptoms of dementia (BPSD). Music therapy has been shown to reduce BPSD. However, no randomised controlled trial has examined the effects of music interventions delivered by caregivers in home settings. The HOME-based caregiver-delivered music intervention for people living with dementia (HOMESIDE) trial aims to evaluate the effectiveness of a 12-week music intervention in addition to standard care for BPSD. This article describes the statistical analysis plan. METHODS AND ANALYSIS: HOMESIDE is a large, pragmatic international three-arm parallel-group randomised controlled trial. Dyads (persons with dementia and caregiver) in Australia, Germany, the UK, Poland and Norway were randomised to receive music and standard care, reading and standard care or standard care alone. The primary outcome is BPSD (proxy) of the person living with dementia, measured using the Neuropsychiatric Inventory-Questionnaire (NPI-Q) at 90 and 180 days post-randomisation. Longitudinal analysis will compare NPI-Q severity between music and standard care versus standard care alone. Secondary outcomes include quality of life and depression (both person with dementia and caregiver), cognition (person with dementia only), distress, resilience, competence and caregiver-patient relationship (caregiver only). Treatment effects will be obtained at 90 and 180 days post-randomisation, where applicable. Safety outcomes (adverse events, hospitalisations, deaths) will be summarised. DISCUSSION: This statistical analysis plan provides a detailed methodology for the analysis of HOMESIDE and will improve the validity of the study and reduce the potential for bias. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618001799246. Registered on November 05, 2018. CLINICALTRIALS: gov NCT03907748. Registered on April 09, 2019.

Clinical and cost effectiveness of a system for turning and positioning intensive care unit patients, when compared to usual care turning and positioning devices, for the prevention of hospital-acquired pressure injuries. A randomised controlled trial.

Pressure injuries affect 13.1% to 45.5% of patients in the intensive care unit and lead to pain and discomfort for patients, burden on healthcare providers, and unnecessary cost to the health system. Turning and positioning systems offer improvements on usual care devices, however the evidence of the effectiveness of such systems is still emerging. We conducted an investigator initiated, prospective, single centre, two group, non-blinded, randomised controlled trial to determine the effectiveness of a system for turning and positioning intensive care unit patients, when compared to usual care turning and positioning devices, for preventing PIs. The trial was prematurely discontinued after enrolment of 78 participants due to COVID-19 pandemic related challenges and lower than expected enrolment rate. The study groups were comparable on baseline characteristics and adherence to the interventions was high. Four participants developed a PI (in the sacral, ischial tuberosity or buttock region), n = 2 each in the intervention and control group. Each participant developed one PI. As the trial is underpowered, these findings do not provide an indication of the clinical effectiveness of the interventions. There was no participant drop-out or withdrawal and there were no adverse events, device deficiencies, or adverse device effects identified or reported. The results of our study (in particular those pertaining to enrolment, intervention adherence and safety) provide considerations for future trials that seek to investigate how to prevent PIs among ICU patients.

A multicomponent psychosocial intervention to reduce substance use by adolescents involved in the criminal justice system: the RISKIT-CJS RCT.

Background: Substance use and offending are related in the context of other disinhibitory behaviours. Adolescents involved in the criminal justice system constitute a particularly vulnerable group, with a propensity to engage in risky behaviour that has long-term impact on their future health and well-being. Previous research of the RISKIT programme provided evidence of a potential effect in reducing substance use and risky behaviour in adolescents. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of a multicomponent psychosocial intervention compared with treatment as usual in reducing substance use for substance-using adolescents involved in the criminal justice system. Design: A mixed-methods, prospective, pragmatic, two-arm, randomised controlled trial with follow-up at 6 and 12 months post randomisation. Setting: The study was conducted across youth offending teams, pupil referral units and substance misuse teams across four areas of England (i.e. South East, London, North West, North East). Participants: Adolescents aged between 13 and 17 years (inclusive), recruited between September 2017 and June 2020. Interventions: Participants were randomised to treatment as usual or to treatment as usual in addition to the RISKIT-Criminal Justice System (RISKIT-CJS) programme. The RISKIT-CJS programme was a multicomponent intervention and consisted of two individual motivational interviews with a trained youth worker (lasting 45 minutes each) and two group sessions delivered over half a day on consecutive weeks. Main outcome measures: At 12 months, we assessed per cent days abstinent from substance use over the previous 28 days. Secondary outcome measures included well-being, motivational state, situational confidence, quality of life, resource use and fidelity of interventions delivered. Results: A total of 693 adolescents were assessed for eligibility, of whom 505 (73%) consented. Of these, 246 (49%) were allocated to the RISKIT-CJS intervention and 259 (51%) were allocated to treatment as usual only. At month 12, the overall follow-up rate was 57%: 55% in the RISKIT-CJS arm and 59% in the treatment-as-usual arm. At month 12, we observed an increase in per cent days abstinent from substances in both arms of the study, from 61% to 85%, but there was no evidence that the RISKIT-CJS intervention was superior to treatment as usual. A similar pattern was observed for secondary outcomes. The RISKIT-CJS intervention was not found to be any more cost-effective than treatment as usual. The qualitative research indicated that young people were positive about learning new skills and acquiring new knowledge. Although stakeholders considered the intervention worthwhile, they expressed concern that it came too late for the target population. Limitations: Our original aim to collect data on offences was thwarted by the onset of the COVID-19 pandemic, and this affected both the statistical and economic analyses. Although 214 (87%) of the 246 participants allocated to the RISKIT-CJS intervention attended at least one individual face-to-face session, 98 (40%) attended a group session and only 47 (19%) attended all elements of the intervention. Conclusions: The RISKIT-CJS intervention was no more clinically effective or cost-effective than treatment as usual in reducing substance use among adolescents involved in the criminal justice system. Future research: The RISKIT-CJS intervention was considered more acceptable, and adherence was higher, in pupil referral units and substance misuse teams than in youth offending teams. Stakeholders in youth offending teams thought that the intervention was too late in the trajectory for their population. Trial registration: This trial is registered as ISRCTN77037777. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information.

We explored how useful a psychological intervention was in reducing substance use among young people who had some involvement in the criminal justice system. We recruited young people aged between 13 and 17 years in four areas of England (i.e. South East, London, North West and North East). Young people were recruited from youth offending teams, pupil referral units and substance misuse teams. Those young people who were willing to participate were offered usual treatment and half, chosen at random, were offered an opportunity to take part in the RISKIT-Criminal Justice System (RISKIT-CJS) programme. The RISKIT-CJS programme had four distinct parts. The first was a 1-hour session that used an approach called motivational interviewing to explore the young person's substance use and discuss different strategies to change their behaviour. This was followed by two group sessions delivered over 2 consecutive weeks. These group sessions addressed risks associated with substance use, what triggers use and the health and social consequences. In addition, young people were taught new skills to help them manage in situations in which they might normally use substances. At the end of the group sessions, the young people had another motivational interview. Twelve months after participants started, we found that the frequency of substance use had decreased in both groups; however, the RISKIT-CJS intervention was no better than treatment as usual. When we spoke with young people who had taken part and staff involved with this population, we got a mixed picture. In some settings, particularly pupil referral units, the RISKIT-CJS intervention was well received by young people and staff, and staff felt that it was a useful additional resource to the work that they were currently undertaking. On the other hand, in the youth offending teams, the staff thought that the programme was too different from their normal work to be implemented easily and they considered the population they work with too established in their substance use and criminal activity to benefit from the programme.

ACT2COPE: A pilot randomised trial of a brief online acceptance and commitment therapy intervention for people living with chronic health conditions during the COVID-19 pandemic

It is well established that the COVID-19 pandemic increased psychological distress in many populations, particularly for people with chronic health conditions (CHCs). Web-based mental health interventions provide a scalable and cost-effective approach to providing psychological support for people disproportionately affected by the COVID-19 pandemic. The current study aimed to explore the feasibility and acceptability of a one-week web-based psychological intervention (ACT2COPE) and explore preliminary effects of the intervention on reducing depression, anxiety, and stress symptoms, and improving wellbeing and psychological flexibility in adults living with CHCs during the COVID-19 pandemic in Aotearoa (New Zealand). A pilot randomised waitlist-controlled trial explored the acceptability and preliminary efficacy of ACT2COPE among 40 participants (n = 20 in the ACT2COPE group and n = 20 in the waitlist control group). Focus groups and open-ended questions explored usability and acceptability of the intervention as well as levels of engagement and adherence to the intervention. Mixed model ANOVAs explored within and between-group differences in psychological outcomes. Qualitative findings suggested that participants found ACT2COPE acceptable and engaging. Depressive symptoms significantly decreased over time compared to the waitlist group at 4-weeks follow-up (p =.012). No other between-group differences were found. The online ACT2COPE intervention presents a promising, scalable intervention that may improve psychological outcomes in adults living with CHCs during the COVID-19 pandemic. Future research is needed to confirm these findings in a larger and more diverse population and over a longer timeframe. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Remote blood pressure monitoring in high risk pregnancy - study protocol for a randomised controlled trial (REMOTE CONTROL trial).

BACKGROUND: Pregnant women at high risk for developing a hypertensive disorder of pregnancy require frequent antenatal assessments, especially of their blood pressure. This expends significant resources for both the patient and healthcare system. An alternative to in-clinic assessments is a remote blood pressure monitoring strategy, in which patients self-record their blood pressure at home using a validated blood pressure machine. This has the potential to be cost-effective, increase patient satisfaction, and reduce outpatient visits, and has had widespread uptake recently given the increased need for remote care during the ongoing COVID-19 pandemic. However robust evidence supporting this approach over a traditional face-to-face approach is lacking, and the impact on maternal and foetal outcomes has not yet been reported. Thus, there is an urgent need to assess the efficacy of remote monitoring in pregnant women at high risk of developing a hypertensive disorder of pregnancy. METHODS: The REMOTE CONTROL trial is a pragmatic, unblinded, randomised controlled trial, which aims to compare remote blood pressure monitoring in high-risk pregnant women with conventional face-to-face clinic monitoring, in a 1:1 allocation ratio. The study will recruit patients across 3 metropolitan Australian teaching hospitals and will evaluate the safety, cost-effectiveness, impact on healthcare utilisation and end-user satisfaction of remote blood pressure monitoring. DISCUSSION: Remote blood pressure monitoring is garnering interest worldwide and has been increasingly implemented following the COVID-19 pandemic. However, robust data regarding its safety for maternofoetal outcomes is lacking. The REMOTE CONTROL trial is amongst the first randomised controlled trials currently underway, powered to evaluate maternal and foetal outcomes. If proven to be as safe as conventional clinic monitoring, major potential benefits include reducing clinic visits, waiting times, travel costs, and improving delivery of care to vulnerable populations in rural and remote communities. TRIAL REGISTRATION: The trial has been prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12620001049965p, on October 11th, 2020).

Use of a novel smartphone-based application tool for enrolment and randomisation in pre-hospital clinical trials.

The effective recruitment and randomisation of patients in pre-hospital clinical trials presents unique challenges. Owing to the time critical nature of many pre-hospital emergencies and limited resourcing, the use of traditional methods of randomisation that may include centralised telephone or web-based systems are often not practicable or feasible. Previous technological limitations have necessitated that pre-hospital trialists strike a compromise between implementing pragmatic, deliverable study designs, with robust enrolment and randomisation methodologies. In this commentary piece, we present a novel smartphone-based solution that has the potential to align pre-hospital clinical trial recruitment processes to that of best-in-practice in-hospital and ambulatory care based studies.

DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function.

BACKGROUND: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. METHODS: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. FINDINGS: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. INTERPRETATION: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04382053.

Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm.

BACKGROUND: Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms. METHODS: MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05). DISCUSSION: Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design. TRIAL REGISTRATION: Australian Clinical Trials ACTRN12618001707257 . Registered on 16 October 2018.

The effectiveness of a computer-aided system in improving the detection rate of gastric neoplasm and early gastric cancer: study protocol for a multi-centre, randomized controlled trial.

BACKGROUND: This protocol is for a multi-centre randomised controlled trial to determine whether the computer-aided system ENDOANGEL-GC improves the detection rates of gastric neoplasms and early gastric cancer (EGC) in routine oesophagogastroduodenoscopy (EGD). METHODS: Study design: Prospective, single-blind, parallel-group, multi-centre randomised controlled trial. SETTINGS: The computer-aided system ENDOANGEL-GC was used to monitor blind spots, detect gastric abnormalities, and identify gastric neoplasms during EGD. PARTICIPANTS: Adults who underwent screening, diagnosis, or surveillance EGD. Randomisation groups: 1. Experiment group, EGD examinations with the assistance of the ENDOANGEL-GC; 2. Control group, EGD examinations without the assistance of the ENDOANGEL-GC. RANDOMISATION: Block randomisation, stratified by centre. PRIMARY OUTCOMES: Detection rates of gastric neoplasms and EGC. SECONDARY OUTCOMES: Detection rate of premalignant gastric lesions, biopsy rate, observation time, and number of blind spots on EGD. BLINDING: Outcomes are undertaken by blinded assessors. SAMPLE SIZE: Based on the previously published findings and our pilot study, the detection rate of gastric neoplasms in the control group is estimated to be 2.5%, and that of the experimental group is expected to be 4.0%. With a two-sided α level of 0.05 and power of 80%, allowing for a 10% drop-out rate, the sample size is calculated as 4858. The detection rate of EGC in the control group is estimated to be 20%, and that of the experiment group is expected to be 35%. With a two-sided α level of 0.05 and power of 80%, a total of 270 cases of gastric cancer are needed. Assuming the proportion of gastric cancer to be 1% in patients undergoing EGD and allowing for a 10% dropout rate, the sample size is calculated as 30,000. Considering the larger sample size calculated from the two primary endpoints, the required sample size is determined to be 30,000. DISCUSSION: The results of this trial will help determine the effectiveness of the ENDOANGEL-GC in clinical settings. TRIAL REGISTRATION: ChiCTR (Chinese Clinical Trial Registry), ChiCTR2100054449, registered 17 December 2021.

Cardiovascular implications and physical activity in middle-aged and older adults with a history of COVID-19 (CV COVID): a protocol for a randomised controlled trial.

BACKGROUND: The clinical manifestation of COVID-19 is associated with infection and inflammation of the lungs, but there is evidence to suggest that COVID-19 may also affect the structure and function of the cardiovascular system. At present, it is not fully understood to what extent COVID-19 impacts cardiovascular function in the short- and long-term following infection. The aim of the present study is twofold: (i) to define the effect of COVID-19 on cardiovascular function (i.e. arterial stiffness, cardiac systolic and diastolic function) in otherwise healthy individuals and (ii) to evaluate the effect of a home-based physical activity intervention on cardiovascular function in people with a history of COVID-19. METHODS: This prospective, single-centre, observational study will recruit 120 COVID-19-vaccinated adult participants aged between 50 and 85 years, i.e. 80 with a history of COVID-19 and 40 healthy controls without a history of COVID-19. All participants will undergo baseline assessments including 12-lead electrocardiography, heart rate variability, arterial stiffness, rest and stress echocardiography with speckle tracking imaging, spirometry, maximal cardiopulmonary exercise testing, 7-day physical activity and sleep measures and quality of life questionnaires. Blood samples will be collected to assess the microRNA expression profiles, cardiac and inflammatory biomarkers, i.e. cardiac troponin T; N-terminal pro B-type natriuretic peptide; tumour necrosis factor alpha; interleukins 1, 6 and 10; C-reactive protein; D-dimer; and vascular endothelial growth factors. Following baseline assessments, COVID-19 participants will be randomised 1:1 into a 12-week home-based physical activity intervention aiming to increase their daily number of steps by 2000 from baseline. The primary outcome is change in left ventricular global longitudinal strain. Secondary outcomes are arterial stiffness, systolic and diastolic function of the heart, functional capacity, lung function, sleep measures, quality of life and well-being (depression, anxiety, stress and sleep efficiency). DISCUSSION: The study will provide insights into the cardiovascular implications of COVID-19 and their malleability with a home-based physical activity intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05492552. Registered on 7 April 2022.

The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

Effectiveness and cost-effectiveness of text messages with or without endowment incentives for weight management in men with obesity (Game of Stones): study protocol for a randomised controlled trial.

BACKGROUND: Obesity increases the risk of type 2 diabetes, heart disease, stroke, mobility problems and some cancers, and its prevalence is rising. Men engage less than women in existing weight loss interventions. Game of Stones builds on a successful feasibility study and aims to find out if automated text messages with or without endowment incentives are effective and cost-effective for weight loss at 12 months compared to a waiting list comparator arm in men with obesity. METHODS: A 3-arm, parallel group, assessor-blind superiority randomised controlled trial with process evaluation will recruit 585 adult men with body mass index of 30 kg/m2 or more living in and around three UK centres (Belfast, Bristol, Glasgow), purposively targeting disadvantaged areas. Intervention groups: (i) automated, theory-informed text messages daily for 12 months plus endowment incentives linked to verified weight loss targets at 3, 6 and 12 months; (ii) the same text messages and weight loss assessment protocol; (iii) comparator group: 12 month waiting list, then text messages for 3 months. The primary outcome is percentage weight change at 12 months from baseline. Secondary outcomes at 12 months are as follows: quality of life, wellbeing, mental health, weight stigma, behaviours, satisfaction and confidence. Follow-up includes weight at 24 months. A health economic evaluation will measure cost-effectiveness over the trial and over modelled lifetime: including health service resource-use and quality-adjusted life years. The cost-utility analysis will report incremental cost per quality-adjusted life years gained. Participant and service provider perspectives will be explored via telephone interviews, and exploratory mixed methods process evaluation analyses will focus on mental health, multiple long-term conditions, health inequalities and implementation strategies. DISCUSSION: The trial will report whether text messages (with and without cash incentives) can help men to lose weight over 1 year and maintain this for another year compared to a comparator group; the costs and benefits to the health service; and men's experiences of the interventions. Process analyses with public involvement and service commissioner input will ensure that this open-source digital self-care intervention could be sustainable and scalable by a range of NHS or public services. TRIAL REGISTRATION: ISRCTN 91974895 . Registered on 14/04/2021.

REACH-ASD: a UK randomised controlled trial of a new post-diagnostic psycho-education and acceptance and commitment therapy programme against treatment-as-usual for improving the mental health and adjustment of caregivers of children recently diagnosed with autism spectrum disorder.

BACKGROUND: Autism is a neurodevelopmental disability affecting over 1% of UK children. The period following a child's autism diagnosis can present real challenges in adaptation for families. Twenty to 50% of caregivers show clinically significant levels of mental health need within the post-diagnostic period and on an ongoing basis. Best practice guidelines recommend timely post-diagnostic family support. Current provision is patchy, largely unevidenced, and a source of dissatisfaction for both families and professionals. There is a pressing need for an evidenced programme of post-diagnostic support focusing on caregiver mental health and adjustment, alongside autism psycho-education. This trial tests the clinical and cost-effectiveness of a new brief manualised psychosocial intervention designed to address this gap. METHODS: This is a multi-centre two-parallel-group single (researcher)-blinded randomised controlled trial of the Empower-Autism programme plus treatment-as-usual versus usual local post-diagnostic offer plus treatment-as-usual. Caregivers of children aged 2-15 years with a recent autism diagnosis will be recruited from North West England NHS or local authority centres. Randomisation is individually by child, with one "index" caregiver per child, stratified by centre, using 2:1 randomisation ratio to assist recruitment and timely intervention. Empower-Autism is a group-based, manualised, post-diagnostic programme that combines autism psycho-education and psychotherapeutic components based on Acceptance and Commitment Therapy to support caregiver mental health, stress management and adjustment to their child's diagnosis. The comparator is any usual local group-based post-diagnostic psycho-education offer. Receipt of services will be specified through health economic data. PRIMARY OUTCOME: caregiver mental health (General Health Questionnaire-30) at 52-week follow-up. SECONDARY OUTCOMES: key caregiver measures (wellbeing, self-efficacy, adjustment, autism knowledge) at 12-, 26- and 52-week follow-up and family and child outcomes (wellbeing and functioning) at 52-week endpoint. SAMPLE: N=380 (approximately 253 intervention/127 treatment-as-usual). Primary analysis will follow intention-to-treat principles using linear mixed models with random intercepts for group membership and repeated measures. Cost-effectiveness acceptability analyses will be over 52 weeks, with decision modelling to extrapolate to longer time periods. DISCUSSION: If effective, this new approach will fill a key gap in the provision of evidence-based care pathways for autistic children and their families. TRIAL REGISTRATION: ISRCTN 45412843 . Prospectively registered on 11 September 2019.

Study protocol for a randomised controlled trial of diacerein versus placebo to treat knee osteoarthritis with effusion-synovitis (DICKENS).

BACKGROUND: There is an unmet need for treatments for knee osteoarthritis (OA). Effusion-synovitis is a common inflammatory phenotype of knee OA and predicts knee pain and structural degradation. Anti-inflammatory therapies, such as diacerein, may be effective for this phenotype. While diacerein is recommended for alleviating pain in OA patients, evidence for its effectiveness is inconsistent, possibly because studies have not targeted patients with an inflammatory phenotype. Therefore, we will conduct a multi-centre, randomised, placebo-controlled double-blind trial to determine the effect of diacerein on changes in knee pain and effusion-synovitis over 24 weeks in patients with knee OA and magnetic resonance imaging (MRI)-defined effusion-synovitis. METHODS: We will recruit 260 patients with clinical knee OA, significant knee pain, and MRI-detected effusion-synovitis in Hobart, Melbourne, Adelaide, and Perth, Australia. They will be randomly allocated to receive either diacerein (50mg twice daily) or identical placebo for 24 weeks. MRI of the study knee will be performed at screening and after 24 weeks of intervention. The primary outcome is improvement in knee pain at 24 weeks as assessed by a 100-mm visual analogue scale (VAS). Secondary outcomes include improvement in volumetric (ml) and semi-quantitative (Whole-Organ Magnetic Resonance Imaging Score, 0-3) measurements of effusion-synovitis using MRI over 24 weeks, and improvement in knee pain (VAS) at 4, 8, 12, 16, and 20 weeks. Intention-to-treat analyses of primary and secondary outcomes will be performed as the primary analyses. Per protocol analyses will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to determine whether diacerein improves pain, changes disease trajectory, and slows disease progression in OA patients with effusion-synovitis. If diacerein proves effective, this has the potential to significantly benefit the substantial proportion (up to 60%) of knee OA patients with an inflammatory phenotype. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12618001656224 . Registered on 08 October 2018.

A Phase II randomised controlled trial of oral prednisolone in early diffuse cutaneous systemic sclerosis (PRedSS).

OBJECTIVES: Although the painful and disabling features of early diffuse cutaneous systemic sclerosis (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate dose prednisolone in early dcSSc. METHODS: PRedSS set out as a Phase II, multicentre, double-blind randomised controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomised to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin core (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients. RESULTS: Thirty-five patients were randomised (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI -0.29-0.10), p= 0.254, and in mRSS -3.90 (97.5% CI -8.83-1.03), p= 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (p= 0.027), anxiety (p= 0.018) and helplessness (p= 0.040) than control patients at 3 months. There were no renal crises, but sample size was small. CONCLUSION: PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomised trial. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718.

The relationship between hand hygiene and rates of acute respiratory infections among Umrah pilgrims: A pilot randomised controlled trial.

BACKGROUND: There is a lack of randomised controlled trials (RCTs) investigating the role of hand hygiene in preventing and containing acute respiratory infections (ARIs) in mass gatherings. In this pilot RCT, we assessed the feasibility of establishing a large-scale trial to explore the relationship between practising hand hygiene and rates of ARI in Umrah pilgrimage amidst the COVID-19 pandemic. METHODS: A parallel RCT was conducted in hotels in Makkah, Saudi Arabia, between April and July 2021. Domestic adult pilgrims who consented to participate were randomised 1:1 to the intervention group who received alcohol-based hand rub (ABHR) and instructions, or to the control group who did not receive ABHR or instructions but were free to use their own supplies. Pilgrims in both groups were then followed up for seven days for ARI symptoms. The primary outcome was the difference in the proportions of syndromic ARIs among pilgrims between the randomised groups. RESULTS: A total of 507 (control: intervention = 267: 240) participants aged between 18 and 75 (median 34) years were randomised; 61 participants were lost to follow-up or withdrew leaving 446 participants (control: intervention = 237:209) for the primary outcome analysis; of whom 10 (2.2 %) had developed at least one respiratory symptom, three (0.7 %) had 'possible ILI' and two (0.4 %) had 'possible COVID-19'. The analysis of the primary outcome found no evidence of difference in the proportions of ARIs between the randomised groups (odds ratio 1.1 [0.3-4.0] for intervention relative to control). CONCLUSION: This pilot trial suggests that conducting a future definitive RCT to assess the role of hand hygiene in the prevention of ARIs is feasible in Umrah setting amidst such a pandemic; however, outcomes from this trial are inconclusive, and such a study would need to be very large given the low rates of outcomes observed here. TRIAL REGISTRATION: This trial was registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12622001287729), the full protocol can be accessed there.

A Systematic Review of the Randomized Controlled Trials of Gemcabene and Its Therapeutic Uses.

Statins are the most widely used drugs for reducing lipid and cholesterol levels in the blood. However, statins have shown some adverse effects and less acceptance among patients; hence, new drugs have been promoted in the market. Furthermore, gemcabenes were discovered in 1995 and are now in phase II and III clinical trials. Gemcabene acts by inhibiting incorporation of 14C-acetate into hepatocytes and stops the mechanism of fatty acids and cholesterol synthesis. In this review the six randomized controlled trials (RCTs) were scrutinized from the two databases by using keywords "Gemcabene" AND "Randomized Controlled Trial." The trials were mainly on animal models, and two studies were found to be associated with human subjects. The study concluded that gemcabene was effective as an anti-inflammatory agent and reduced lipid levels and the progression of fibrosis. Hence, further controlled trials are needed to determine its efficacy and safety in human subjects, along with the identification of adverse effects.