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.

Ambulatory blood pressure monitoring using telemedicine: proof-of-concept cohort and failure modes and effects analyses.

Background: The COVID-19 pandemic has accelerated adoption of remote consulting in healthcare. Despite opportunities posed by telemedicine, most hypertension services in Europe have suspended ambulatory blood pressure monitoring (ABPM). Methods: We examined the process and performance of remotely delivered ABPM using two methodologies: firstly, a Failure Modes and Effects Analysis (FMEA) and secondly, a quantitative analysis comparing ABPM data from a subgroup of 65 participants of the Screening for Hypertension in the INpatient Environment (SHINE) diagnostic accuracy study. The FMEA was performed over seven sessions from February to March 2021, with a multidisciplinary team comprising a patient representative, a research coordinator with technical expertise and four research clinicians. Results: The FMEA identified a single high-risk step in the remote ABPM process. This was cleaning of monitoring equipment in the context of the COVID-19 pandemic, unrelated to the remote setting. A total of 14 participants were scheduled for face-to-face ABPM appointments, before the UK March 2020 COVID-19 lockdown; 62 were scheduled for remote ABPM appointments since emergence of the COVID-19 pandemic between November 2020 and August 2021. A total of 65 (88%) participants completed ABPMs; all obtained sufficient successful measurements for interpretation. For the 10 participants who completed face-to-face ABPM, there were 402 attempted ABPM measurements and 361 (89%) were successful. For the 55 participants who completed remote ABPM, there were 2516 attempted measurements and 2114 (88%) were successful. There was no significant difference in the mean per-participant error rate between face-to-face (0.100, SD 0.009) and remote (0.143, SD 0.132) cohorts (95% CI for the difference -0.125 to 0.045 and two-tailed P-value 0.353). Conclusions: We have demonstrated that ABPM can be safely and appropriately provided in the community remotely and without face-to-face contact, using video technology for remote fitting appointments, alongside courier services for delivery of equipment to participants.

Ambulatory blood pressure monitoring using telemedicine: proof-of-concept cohort and failure modes and effects analyses [version 3;peer review: 2 approved]

Background: The COVID-19 pandemic has accelerated adoption of remote consulting in healthcare. Despite opportunities posed by telemedicine, most hypertension services in Europe have suspended ambulatory blood pressure monitoring (ABPM). Methods: We examined the process and performance of remotely delivered ABPM using two methodologies: firstly, a Failure Modes and Effects Analysis (FMEA) and secondly, a quantitative analysis comparing ABPM data from a subgroup of 65 participants of the Screening for Hypertension in the INpatient Environment (SHINE) diagnostic accuracy study. The FMEA was performed over seven sessions from February to March 2021, with a multidisciplinary team comprising a patient representative, a research coordinator with technical expertise and four research clinicians. Results: The FMEA identified a single high-risk step in the remote ABPM process. This was cleaning of monitoring equipment in the context of the COVID-19 pandemic, unrelated to the remote setting. A total of 14 participants were scheduled for face-to-face ABPM appointments, before the UK March 2020 COVID-19 lockdown;62 were scheduled for remote ABPM appointments since emergence of the COVID-19 pandemic between November 2020 and August 2021. A total of 65 (88%) participants completed ABPMs;all obtained sufficient successful measurements for interpretation. For the 10 participants who completed face-to-face ABPM, there were 402 attempted ABPM measurements and 361 (89%) were successful. For the 55 participants who completed remote ABPM, there were 2516 attempted measurements and 2214 (88%) were successful. There was no significant difference in the mean per-participant error rate between face-to-face (0.100, SD 0.009) and remote (0.143, SD 0.132) cohorts (95% CI for the difference -0.125 to 0.045 and two-tailed P-value 0.353). Conclusions: We have demonstrated that ABPM can be safely and appropriately provided in the community remotely and without face-to-face contact, using video technology for remote fitting appointments, alongside courier services for delivery of equipment to participants.

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.