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BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absent in vitro activity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended. MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10 viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In a post hoc subgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: -21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants. ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reduced in vitro activities, casirivimab/imdevimab retains in vivo antiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants. Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.
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BackgroundThere is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain. MethodsIn a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600{micro}g/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907). ResultsRandomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41]. ConclusionsHigh dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 therapeutics in vivo. Funding"Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)" is funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z). ImpactO_LIRate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection. C_LIO_LIHigh dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection. C_LI
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Pakistan Registry of Intensive Care (PRICE) is a platform that has enabled standardized COVID-19 clinical data collection based on ISARIC/WHO Clinical Characterization Protocol. The near real-time data platform includes epidemiology, severity of illness, microbiology, treatment and outcomes of patients admitted with suspected or laboratory confirmed COVID19 infection to 67 intensive care and high dependency units across the country. Data has been extracted and analysed at regular intervals to inform stakeholders and improve care practices. This is our 28th report including all patients with suspected or confirmed COVID-19 from 26th March 2020 to 26th December 2021. Key findings from 8624 patients who met eligibility criteria, are as follows: Median age of 60 years (IQR 50-70). The most common symptoms were shortness of breath (n = 6428, 77.8%), fever (n = 6091, 73.8%), and Cough (n = 3354, 38.9%) The most common comorbidity was hypertension followed by diabetes. During the course of illness 2804 (32.6%) patients received non-invasive ventilation, whereas 2474 (28.8%) patients had mechanical ventilation as their highest organ support. In addition, 2246 (26.1%) patients needed haemodynamic support and 1249 (14.7%) patients required renal replacement therapy as their highest organ support. Median APACHE II score was 18 Overall mortality at ICU discharge was 39.2% Increasing age and requirement for invasive mechanical ventilation were independent risk factors for mortality increased the risk of death