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.

Cost-utility analysis of molnupiravir plus usual care versus usual care alone as early treatment for community-based adults with COVID-19 and increased risk of adverse outcomes in the UK 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 six months. DESIGN AND SETTING: Economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK National Health Service and personal social services perspective and a six-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 0.004 to 0.007) than usual care (mean incremental cost per QALY of £81190). Sensitivity and subgroup analyses showed similar results, except those aged ≥75 years with a 55% probability of being cost-effective at a £30000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15000 per QALY threshold. CONCLUSION: Molnupiravir at the current cost of £513 per course is unlikely to be cost-effective relative to usual care over a six-month time horizon among mainly vaccinated COVID-19 patients at increased risk of adverse outcomes, except those aged ≥75 years.

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease.

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

Inhaled Budesonide for COVID-19 in People at Higher Risk of Complications in the Community: The UK National Community Randomi.

Background The effectiveness of repurposed treatments with supportive evidence for higher risk individuals with COVID-19 in the community is unknown. In the UK PRINCIPLE national platform trial we aimed to determine whether 're-purposed medicines' (hydroxychloroquine, azithromycin, doxycycline, colchicine, inhaled budesonide, and other interventions) reduced time to recovery and COVID-19 related hospitalisations/deaths among people at higher risk of COVID-19 complications in the community. We mainly report the findings for budesonide arm here. Methods Participants in this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial were aged ≥65, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community, and were randomised to usual care, usual care plus inhaled budesonide (800µg twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Trial registration: ISRCTN86534580. Funded by United Kingdom Research Innovation (MC_PC_19079). Findings The trial opened on April 2, 2020, with the first 4 intervention arms stopped on futility grounds. Randomisation to the budesonide arm occurred from November 27, 2020 until March 31, 2021, when the pre-specified time to recovery superiority criterion was met. The primary analysis model includes 2530 SARS-CoV-2 positive participants, randomised to budesonide (n=787), usual care (n=1069), and other treatments (n=674). Time to first self-reported recovery was shorter in the budesonide group versus usual care (hazard ratio 1·21 [95% credible interval 1·08 to 1·36], probability of superiority >O·999, estimated benefit 2·94 [95% credible interval 1·19 to 5·12] days). An estimated 6·8% COVID-19 related hospitalisations/deaths occurred in the budesonide group versus 8·8% in usual care (estimated absolute difference, 2·0% [95% credible interval -0.2% to 4.5%], probability of superiority 0.963). In the main secondary analysis of admissions using only concurrent controls, admissions occurred in 6.6% (3.8 to 10.1%) in the budesonide group versus 8.8% (95% CI 5.2 to 13.1%), with an absolute difference of 2.2% (0.0 to 4.9%) and a hazard ratio of 0.73 (0.53 to 1.00), meeting the pre-specified superiority probability of 0.975. Three serious adverse events occurred in the budesonide group and three in usual care.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

Enhancing opportunistic recruitment and retention in primary care trials: lessons learned from a qualitative study embedded in the Cranberry for Urinary Tract Infection (CUTI) feasibility trial.

BACKGROUND: Opportunistic recruitment in primary care is challenging due to the inherent unpredictability of incident conditions, and workload and time pressures. Many clinical trials do not recruit to target, leading to equivocal answers to research questions. Learning from the experiences of patients and recruiters to trials of incident conditions has the potential to improve recruitment and retention to future trials, thereby enhancing the quality and impact of research findings. The aim of this research was to learn from the trial experiences of UTI patients and recruiters to the Cranberry for UTI (CUTI) trial, to help plan an adequately powered trial of similar design. METHODS: One-to-one semi-structured interviews were embedded within the CUTI feasibility trial, an open-label, randomised feasibility trial of cranberry extract for symptoms of acute, uncomplicated Urinary Tract Infection (UTI) in primary care. Interviews were conducted with a sample of: CUTI trial participants; non-CUTI trial UTI patients; and, recruiters to the CUTI trial. Verbatim transcripts were analysed thematically. RESULTS: Twenty-six patients with UTI and eight recruiters (nurses and GPs) to the CUTI trial were interviewed. Three themes were developed around: reasons for participating in research; barriers to opportunistic recruitment; and, UTI patients' experiences of trial procedures. Recruiters found that targeted electronic prompts directed at healthcare practitioners based in clinics where patients with incident conditions were likely to present (e.g. minor illness clinic) were more effective than generic prompts (e.g. desk prompts) at filtering patients from their usual clinical pathway to research clinics. Using a script to explain the delayed antibiotic trial group to patients was found to be helpful, and may have served to boost recruitment. For UTI patients, using an electronic diary to rate their symptoms was considered an acceptable medium, and often preferable to using a paper diary or mobile phone application. CONCLUSIONS: The use of targeted prompts directed at clinicians, a script to explain trial groups that may be deemed less desirable, and an appropriate diary format for patient-reported outcomes, may help to improve trial recruitment and retention.

Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial.

BACKGROUND: Colchicine has been proposed as a COVID-19 treatment. AIM: To determine whether colchicine reduces time to recovery and COVID-19-related admissions to hospital and/or deaths among people in the community. DESIGN AND SETTING: Prospective, multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial (PRINCIPLE). METHOD: Adults aged ≥65 years or ≥18 years with comorbidities or shortness of breath, and unwell for ≤14 days with suspected COVID-19 in the community, were randomised to usual care, usual care plus colchicine (500 µg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery and admission to hospital/death related to COVID-19, within 28 days, analysed using Bayesian models. RESULTS: The trial opened on 2 April 2020. Randomisation to colchicine started on 4 March 2021 and stopped on 26 May 2021 because the prespecified time to recovery futility criterion was met. The primary analysis model included 2755 participants who were SARS-CoV-2 positive, randomised to colchicine (n = 156), usual care (n = 1145), and other treatments (n = 1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.92 (95% credible interval (CrI) = 0.72 to 1.16) and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. COVID-19-related admissions to hospital/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 (95% CrI = 0.28 to 1.89) and an estimated difference of -0.4% (95% CrI = -2.7 to 2.4). CONCLUSION: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

Non-antibiotic treatment of acute urinary tract infection in primary care: a qualitative study.

BACKGROUND: The views of women with acute, uncomplicated urinary tract infection (auUTI) on the acceptability of non-antibiotic treatment options are poorly understood. AIM: To establish women's thoughts on and experience of non-antibiotic treatment for auUTIs. DESIGN AND SETTING: Qualitative interview study with primary care patients in Oxfordshire, UK, embedded within the Cranberry for Urinary Tract Infection (CUTI) feasibility trial. METHOD: One-to-one, semi-structured interviews were conducted between August 2019 and January 2020 with some CUTI trial participants and some patients who were not part of the CUTI trial who had experienced at least one urinary tract infection (UTI) in the preceding 12 months in Oxfordshire, UK. Interviews were analysed using thematic analysis. RESULTS: In total, 26 interviews were conducted and analysed. Women expected to receive an immediate antibiotic for their UTI but were aware of the potential harms of this approach. They were keen to find a non-antibiotic, 'natural' alternative that could effectively manage their symptoms. In certain situations (early illness, milder illness, and with no important upcoming engagements), women indicated they would be prepared to postpone antibiotic treatment by up to 3 days, especially if offered an interim non-antibiotic option with perceived therapeutic potential. CONCLUSION: Many women with auUTIs are open to trying non-antibiotic treatments first in certain situations. There is scope for more dialogue between primary care clinicians and patients with auUTI around delaying antibiotic treatment and using non-antibiotic options initially, which could reduce antibiotic consumption for this common infection.

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.

Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes. METHODS: We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580. FINDINGS: The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI -0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference -0·5% [95% BCI -2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group. INTERPRETATION: In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19. FUNDING: UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research.

Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk.

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

Does cranberry extract reduce antibiotic use for symptoms of acute uncomplicated urinary tract infections (CUTI)? A feasibility randomised trial.

OBJECTIVES: To determine the feasibility of conducting a randomised trial of the effectiveness of cranberry extract in reducing antibiotic use by women with symptoms of acute, uncomplicated urinary tract infection (UTI). DESIGN: Open-label feasibility randomised parallel group trial. SETTING: Four general practices in Oxfordshire. PARTICIPANTS: Women aged 18 years and above presenting to general practice with symptoms of acute, uncomplicated UTI. INTERVENTIONS: Women were randomly assigned using Research Electronic Data Capture in a 1:1:1 ratio to: (1) immediate antibiotics alone (n=15); (2) immediate antibiotics and immediate cranberry capsules for up to 7 days (n=15); or (3) immediate cranberry capsules and delayed antibiotics for self-initiation in case of non-improvement or worsening of symptoms (n=16). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures were: rate of recruitment of participants; numbers lost to follow-up; proportion of electronic diaries completed by participants; and acceptability of the intervention and study procedures to participants and recruiters. Secondary outcomes included an exploration of differences in symptom burden and antibiotic use between groups. RESULTS: Four general practitioner practices (100%) were opened and recruited participants between 1 July and 2 December 2019, with nine study participants recruited per month on average. 68.7% (46/67) of eligible participants were randomised (target 45) with a mean age of 48.4 years (SD 19.9, range 18-81). 89.1% (41/46) of diaries contained some participant entered data and 69.6% (32/46) were fully complete. Three participants (6.5%) were lost to follow-up and two (4.4%) withdrew. Of women randomly assigned to take antibiotics alone (controls), one-third of respondents reported consuming cranberry products (33.3%, 4/12). There were no serious adverse events. CONCLUSIONS: It appears feasible to conduct a randomised trial of the use of cranberry extract in the treatment of acute, uncomplicated UTI in general practice. TRIAL REGISTRATION NUMBER: ISRCTN Registry (ID: 10399299).

Cranberry Extract for Symptoms of Acute, Uncomplicated Urinary Tract Infection: A Systematic Review.

BACKGROUND: Effective alternatives to antibiotics for alleviating symptoms of acute infections may be appealing to patients and enhance antimicrobial stewardship. Cranberry-based products are already in wide use for symptoms of acute urinary tract infection (UTI). The aim of this review was to identify and critically appraise the supporting evidence. METHODS: The protocol was registered on PROSPERO. Searches were conducted of Medline, Embase, Amed, Cinahl, The Cochrane library, Clinicaltrials.gov and WHO International Clinical Trials Registry Platform. We included randomised clinical trials (RCTs) and non-randomised studies evaluating the effect of cranberry extract in the management of acute, uncomplicated UTI on symptoms, antibiotic use, microbiological assessment, biochemical assessment and adverse events. Study risk of bias assessments were made using Cochrane criteria. RESULTS: We included three RCTs (n = 688) judged to be at moderate risk of bias. One RCT (n = 309) found that advice to consume cranberry juice had no statistically significant effect on UTI frequency symptoms (mean difference (MD) -0.01 (95% CI: -0.37 to 0.34), p = 0.94)), on UTI symptoms of feeling unwell (MD 0.02 (95% CI: -0.36 to 0.39), p = 0.93)) or on antibiotic use (odds ratio 1.27 (95% CI: 0.47 to 3.43), p = 0.64), when compared with promoting drinking water. One RCT (n = 319) found no symptomatic benefit from combining cranberry juice with immediate antibiotics for an acute UTI, compared with placebo juice combined with immediate antibiotics. In one RCT (n = 60), consumption of cranberry extract capsules was associated with a within-group improvement in urinary symptoms and Escherichia coli load at day 10 compared with baseline (p < 0.01), which was not found in untreated controls (p = 0.72). Two RCTs were under-powered to detect differences between groups for outcomes of interest. There were no serious adverse effects associated with cranberry consumption. CONCLUSION: The current evidence base for or against the use of cranberry extract in the management of acute, uncomplicated UTIs is inadequate; rigorous trials are needed.

The protease inhibitor lopinavir, boosted with ritonavir, as treatment for COVID-19: a rapid review.

BACKGROUND: The HIV protease inhibitor lopinavir, boosted with ritonavir, has been used off-label to treat COVID-19. We aimed to synthesize the clinical evidence for lopinavir/ritonavir as a treatment for COVID-19. METHODS: We performed a rapid review by searching databases including PubMed, GoogleScholar, medRxiv, ClinicalTrials.gov and the Cochrane COVID-19 Study Register, for COVID-19 studies comparing outcomes between patients who did and did not receive lopinavir/ritonavir. The quality of evidence was assessed using the GRADE criteria. RESULTS: We identified five completed randomized controlled trials (RCTs) and 14 retrospective cohort studies. Two large RCTs of 5,040 and 2,771 hospitalized adults with COVID-19 found no evidence that lopinavir/ritonavir influenced the primary outcome of mortality, or secondary outcomes including progression to mechanical ventilation or time to discharge. Results remained similar in all sub-group analyses including by age, gender, baseline ventilation and time since symptom onset. The three smaller RCTs (n=86-199) also found no evidence of a benefit in the primary outcomes of time to clinical improvement or time to viral clearance. The 14 observational studies included between 50 and 415 participants, and were limited by a lack of adjustment for potential confounding variables. The majority of these studies found no evidence that lopinavir/ritonavir was associated with improved mortality or other clinical outcomes, although results regarding viral clearance were mixed. CONCLUSIONS: Good evidence from large clinical trials does not support using lopinavir/ritonavir to treat COVID-19 amongst hospitalized patients.

Does cranberry extract reduce antibiotic use for symptoms of acute uncomplicated urinary tract infections (CUTI)? Protocol for a feasibility study.

BACKGROUND: Consultations in primary care for symptoms of urinary tract infections (UTIs) are common and patients are frequently treated with antibiotics. Given increasing antimicrobial resistance, there has been interest in non-antibiotic treatment options for common infections. One such option is the use of cranberry extract to treat symptoms attributable to UTIs. METHODS: A target of 45 women consulting in primary care, with symptoms suggestive of an uncomplicated UTI for whom the practitioner would normally prescribe antibiotics, will be randomised to receive one of three treatment approaches: (1) immediate prescription for antibiotics; (2) immediate prescription for antibiotics plus a 7-day course of cranberry capsules and (3) cranberry capsules plus a delayed prescription for antibiotics to be used in case their symptoms do not get better, or get worse. Follow-up will be by daily rating of symptoms and recording of treatments used for 2 weeks in an online symptom diary. Interviews will be conducted with around 10-15 study participants, as well as with around 10-15 women who have experienced a UTI but have not been approached to take part in the study. Both groups will be asked about their experience of having a UTI, their thoughts on non-antibiotic treatments for UTIs and their thoughts on, or experience of, the feasibility trial. The primary objective is to assess the feasibility of undertaking a full trial in primary care of the effectiveness of cranberry extract to reduce antibiotic use for symptoms of acute uncomplicated UTI. The secondary objective is to conduct a preliminary assessment of the extent to which cranberry might reduce antibiotic use and symptom burden. DISCUSSION: This feasibility study with embedded interviews will inform the planning and sample size calculation of an adequately powered trial to definitively determine whether cranberry helps to alleviate the symptoms of acute uncomplicated UTIs in women and whether it can safely reduce antibiotic use. TRIAL REGISTRATION: ISRCTN registry, ID: 10399299. Registered on 24 January 2019.

Long-term effects of functional appliances in treated versus untreated patients with Class II malocclusion: A systematic review and meta-analysis.

OBJECTIVE: To assess the cephalometric skeletal and soft-tissue of functional appliances in treated versus untreated Class II subjects in the long-term (primarily at the end of growth, secondarily at least 3 years after retention). SEARCH METHODS: Unrestricted electronic search of 24 databases and additional manual searches up to March 2018. SELECTION CRITERIA: Randomised and non-randomised controlled trials reporting on cephalometric skeletal and soft-tissue measurements of Class II patients (aged 16 years or under) treated with functional appliances, worn alone or in combination with multi-bracket therapy, compared to untreated Class II subjects. DATA COLLECTION AND ANALYSIS: Mean differences (MDs) and 95% confidence intervals (95% CIs) were calculated with the random-effects model. Data were analysed at 2 primary time points (above 18 years of age, at the end of growth according to the Cervical Vertebral Maturation method) and a secondary time point (at least 3 years after retention). The risk of bias and quality of evidence were assessed according to the ROBINS tool and GRADE system, respectively. RESULTS: Eight non-randomised studies published in 12 papers were included. Functional appliances produced a significant improvement of the maxillo-mandibular relationship, at almost all time points (Wits appraisal at the end of growth, MD -3.52 mm, 95% CI -5.11 to -1.93, P < 0.0001). The greatest increase in mandibular length was recorded in patients aged 18 years and above (Co-Gn, MD 3.20 mm, 95% CI 1.32 to 5.08, P = 0.0009), although the improvement of the mandibular projection was negligible or not significant. The quality of evidence was 'very low' for most of the outcomes at both primary time points. CONCLUSIONS: Functional appliances may be effective in correcting skeletal Class II malocclusion in the long-term, however the quality of the evidence was very low and the clinical significance was limited. SYSTEMATIC REVIEW REGISTRATION: CRD42018092139.

Biomarkers for diagnosing serious bacterial infections in older outpatients: a systematic review.

BACKGROUND: The value of biomarkers for diagnosing bacterial infections in older outpatients is uncertain and limited official guidance exists for clinicians in this area. The aim of this review is to critically appraise and evaluate biomarkers for diagnosing bacterial infections in older adults (aged 65 years and above). METHODS: We searched Medline, Embase, Web of Science and the Cochrane Library, from inception to January 2018. We included studies assessing the diagnostic accuracy of blood, urinary, and salivary biomarkers in diagnosing bacterial infections in older adults. The QUADAS-2 tool was used to assess study quality. RESULTS: We identified 11 eligible studies of moderate quality (11,034 participants) including 51 biomarkers at varying thresholds for diagnosing bacterial infections. An elevated Procalcitonin (≥ 0.2 ng/mL) may help diagnose bacteraemia in older adults [+ve LR range 1.50 to 2.60]. A CRP ≥ 50 mg/L only raises the probability of bacteraemia by 5%. A positive urine dipstick aids diagnosis of UTI (+ve LR range 1.23 to 54.90), and absence helps rule out UTI (-ve LR range 0.06 to 0.46). An elevated white blood cell count is unhelpful in diagnosing intra-abdominal infections (+ve LR range 0.75 to 2.62), but may aid differentiation of bacterial infection from other acute illness (+ve LR range 2.14 to 7.12). CONCLUSIONS: The limited available evidence suggests that many diagnostic tests useful in younger patients, do not help to diagnose bacterial infections in older adults. Further evidence from high quality studies is urgently needed to guide clinical practice. Until then, symptoms and signs remain the mainstay of diagnosis in community based populations.

Limited evidence for diagnosing bacterial skin infections in older adults in primary care: systematic review.

BACKGROUND: Older adults with bacterial skin infections may present with atypical symptoms, making diagnosis difficult. There is limited authoritative guidance on how older adults in the community present with bacterial skin infections. To date there have been no systematic reviews assessing the diagnostic value of symptoms and signs in identifying bacterial skin infections in older adults in the community. METHODS: We searched Medline and Medline in process, Embase and Web of Science, from inception to September 2017. We included cohort and cross-sectional studies assessing the diagnostic accuracy of symptoms and signs in predicting bacterial skin infections in adults in primary care aged over 65 years. The QUADAS-2 tool was used to assess study quality. RESULTS: We identified two observational studies of low-moderate quality, with a total of 7991 participants, providing data to calculate the diagnostic accuracy of 5 unique symptoms in predicting bacterial skin infections. The presence of wounds [LR+: 7.93 (CI 4.81-13.1)], pressure sores [LR+: 4.85 (CI 2.18-10.8)] and skin ulcers [LR+: 6.26 (CI 5.49-7.13)] help to diagnose bacterial skin infections. The presence of urinary incontinence does not help to predict bacterial skin infections (LR + 's of 0.99 and 1.04; LR-'s of 0.96 and 1.04). CONCLUSIONS: Currently, there is insufficient evidence to inform the diagnosis of bacterial skin infections in older adults in the community; clinicians should therefore rely upon their clinical judgement and experience. Evidence from high quality primary care studies in older adults, including studies assessing symptoms traditionally associated with bacterial skin infections (e.g. erythema and warmth), is urgently needed to guide practice.