Abstract Background Here we report on a process evaluation conducted as part of a large multisite non-randomised trial of the effectiveness of a whole genome sequence report form (SRF) to reduce nosocomial SARS-CoV-2 through changing infection prevention and control (IPC) behaviours during the COVID − 19 pandemic. We detail how the SRF was implemented across a heterogeneous purposive sub-sample of hospital trial sites (n = 5/14). Methods We conducted in-depth interviews from diverse professional staff (N = 39). Inductive thematic analysis initially explored participants’ accounts of implementing the SRF. The resulting data driven themes, concerning the way the SRF was used within sites, were then coded in relation to the key tenets of normalisation process theory (NPT). Results Factors that enabled the implementation of the SRF included: elements of the context such as health care professional passion; the existence of whole genome sequencing (WGS) infrastructure; effective communication channels, the creation of new connections across professionals and teams; the integration of SRF-led discussions within pre-existing meetings and the ability of a site to achieve a rapid turnaround time. In contrast, we found factors that constrained the use of the SRF included elements of the context such as the impact of the Alpha-variant overwhelming hospitals. In turn, dealing with COVID-19 breached the limited capacity of infection prevention and control (IPC) to respond to the SRF and ensure its routinisation. Conclusion We show preliminary support for the SRF being an acceptable, useable and potentially scalable way of enhancing existing IPC activities. However, the context of both the trial and the alpha wave of COVID-19 limit these insights. Clinical trial number https://www.isrctn.com/ISRCTN50212645, Registration date 20/05/2020

We appreciate the opportunity to address the concerns of Winston et al , as their unique perspective is certainly germane to this ongoing discussion.[1][1] To clarify, our study[2][2] does not suggest that liposomal bupivacaine has no advantage over plain bupivacaine. Rather, our aim was to assess

We thank Kurhekar et al for their interest in our article and their commentary regarding our research.[1 2][1] We would like to address both of their concerns. First, there are very few studies which directly compare the use of liposomal bupivacaine (LB) to plain bupivacaine with dexamethasone in

Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data collection period, followed by intervention periods comprising 8 weeks of 'rapid' (<48 hr) and 4 weeks of 'longer-turnaround' (5-10 days) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital-onset COVID-19 infections (HOCIs; detected ≥48 hr from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on the incidence of probable/definite hospital-acquired infections (HAIs), was evaluated. A total of 2170 HOCI cases were recorded from October 2020 to April 2021, corresponding to a period of extreme strain on the health service, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (incidence rate ratio 1.60, 95% CI 0.85-3.01; p=0.14) or rapid (0.85, 0.48-1.50; p=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8 and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2 and 11.6% of cases where the report was returned. In a 'per-protocol' sensitivity analysis, there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Capacity to respond effectively to insights from sequencing was breached in most sites by the volume of cases and limited resources. While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days. COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (grant code: MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. NCT04405934.

Background:Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings.Methods:We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data collection period, followed by intervention periods comprising 8 weeks of ‘rapid’ (<48 hr) and 4 weeks of ‘longer-turnaround’ (5–10 days) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital-onset COVID-19 infections (HOCIs; detected ≥48 hr from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on the incidence of probable/definite hospital-acquired infections (HAIs), was evaluated.Results:A total of 2170 HOCI cases were recorded from October 2020 to April 2021, corresponding to a period of extreme strain on the health service, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (incidence rate ratio 1.60, 95% CI 0.85–3.01; p=0.14) or rapid (0.85, 0.48–1.50; p=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8 and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2 and 11.6% of cases where the report was returned. In a ‘per-protocol’ sensitivity analysis, there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Capacity to respond effectively to insights from sequencing was breached in most sites by the volume of cases and limited resources.Conclusions:While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days.Funding:COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (grant code: MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute.Clinical trial number:NCT04405934.

Abstract Background Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. Methods Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a one-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. Results We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement Discussion Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported. Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days. ClinicalTrials.gov Identifier: NCT04452318.

Importance:Easy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage.Objective:Evaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19.Design:Randomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2–infected household member (index case). Participants who were SARS-CoV-2 RT-qPCR–positive at baseline were included in the analysis reported here.Setting:Multicenter trial conducted at 112 sites in the United States, Romania, and Moldova.Participants:Asymptomatic individuals ≥12 years of age were eligible if identified within 96 hours of collection of the index case’s positive SARS-CoV-2 test sample.Interventions:A total of 314 asymptomatic, SARS-CoV-2 RT-qPCR–positive individuals living with an infected household contact were randomized 1:1 to receive a single dose of subcutaneous REGEN-COV 1200mg (n=158) or placebo (n=156).Main Outcome(s) and Measure(s):The primary endpoint was the proportion of participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy endpoints were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Safety was assessed in all treated participants.Results:Subcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs 44/104 [42.3%], respectively; P=.0380). REGEN-COV reduced the overall population burden of high–viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010) and of symptomatic weeks (45.3% reduction vs placebo; 89.6 vs 170.3 total weeks; P=.0273), the latter corresponding to an approximately 5.6-day reduction in symptom duration per symptomatic participant. Six placebo-treated participants had a COVID-19–related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had ≥1 treatment-emergent adverse events was 48.1% compared with 33.5% for those receiving REGEN-COV, including events related (39.7% vs 25.8%, respectively) or not related (16.0% vs 11.0%, respectively) to COVID-19.Conclusions and Relevance:Subcutaneous REGEN-COV 1200mg prevented progression from asymptomatic SARS-CoV-2 infection to COVID-19, reduced the duration of high viral load and symptoms, and was well tolerated.Trial Registration:ClinicalTrials.gov Identifier, NCT04452318

BackgroundREGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.MethodsWe randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-CoV-2 infection (as measured by reverse-transcriptase–quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity).ResultsSymptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted.ConclusionsSubcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.)

Background:Casirivimab and imdevimab (REGEN-COV™) markedly reduces risk of hospitalization or death in high-risk individuals with Covid-19. Here we explore the possibility that subcutaneous REGEN-COV prevents SARS-CoV-2 infection and subsequent Covid-19 in individuals at high risk of contracting SARS-CoV-2 by close exposure in a household with a documented SARS-CoV-2–infected individual.Methods:Individuals ≥12 years were enrolled within 96 hours of a household contact being diagnosed with SARS-CoV-2 and randomized 1:1 to receive 1200 mg REGEN-COV or placebo via subcutaneous injection. The primary efficacy endpoint was the proportion of participants without evidence of infection (SARS-CoV-2 RT-qPCR–negative) or prior immunity (seronegative) who subsequently developed symptomatic SARS-CoV-2 infection during a 28-day efficacy assessment period.Results:Subcutaneous REGEN-COV significantly prevented symptomatic SARS-CoV-2 infection compared with placebo (81.4% risk reduction; 11/753 [1.5%] vs. 59/752 [7.8%], respectively; P<0.0001), with 92.6% risk reduction after the first week (2/753 [0.3%] vs. 27/752 [3.6%], respectively). REGEN-COV also prevented overall infections, either symptomatic or asymptomatic (66.4% risk reduction). Among infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV vs. placebo (1.2 vs. 3.2 weeks, respectively), and the duration of time with high viral load (>104 copies/mL) was lower (0.4 vs. 1.3 weeks, respectively). REGEN-COV was generally well tolerated.Conclusions:Administration of subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in uninfected household contacts of infected individuals. Among individuals who became infected, REGEN-COV reduced the duration of symptomatic disease, decreased maximal viral load, and reduced the duration of detectable virus.(ClinicalTrials.gov number, NCT04452318.)