Search

Background: the antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.Methods: this randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing.Findings: between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial.Interpretation: we found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive.Funding: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Background— The coronary sinus (CS) has a myocardial coat (CSMC) with extensive connections to the left and right atria. We postulated that some posteroseptal and left posterior accessory pathways (CSAPs) result from connections between a cuff of CSMC extending along the middle cardiac vein (MCV) or posterior coronary vein (PCV) and the ventricle. The purpose of the present study was to use CS angiography and mapping to define and determine the incidence of CSAPs and determine the relationship to CS anatomy. Methods and Results— CSAP was defined by accessory pathway (AP) potential or earliest activation in the MCV or PCV and late activation at anular endocardial sites. A CSAP was identified in 171 of 480 patients undergoing ablation of a posteroseptal or left posterior AP. CS angiography revealed a CS diverticulum in 36 (21%) and fusiform or bulbous enlargement of the small cardiac vein, MCV, or CS in 15 (9%) patients. The remaining 120 (70%) patients had an angiographically normal CS. A CSMC extension potential (CSE), like an AP potential, was recorded in the MCV in 98 (82%), in the PCV in 13 (11%), in both the MCV and PCV in 6 (5%), and in the CS in 3 (2%) of 120 patients. CSMC potentials were recorded between the timing of atrial and CSE potentials. Conclusions— CSAPs result from a connection between a CSMC extension (along the MCV or PCV) and the ventricle. The CS is angiographically normal in most patients.

Background— The purpose of this study was to measure the extent of left atrial–pulmonary vein (LA-PV) connections and determine the relation to PV firing in patients with atrial fibrillation (AF). Methods and Results— Ten close-bipolar (1 mm-spacing) Lasso electrograms were recorded circumferentially around 210 PVs (excluding 2 right middle PVs and 4 left common trunks) in 62 patients with AF. PV firing was provoked by isoproterenol (4 μg/min) and cardioversion of pacing-induced AF. The width of each LA-PV connection was measured in tenths of PV circumference, based on number of continuous close-bipolar Lasso electrode sites required for ablation (10% for each close-bipolar electrode site). One, 2, or 3 to 4 discrete LA-PV connections (discrete connection defined by ablation along 10% to 30% of PV circumference) were present in 18 (9%), 31 (14%), and 32 (15%) of 210 PVs, respectively: 1 broad connection (ablation along continuous 40% to 80% circumference) in 46 (22%) PVs; 1 broad plus other broad or discrete connections in 54 (26%) PVs; and a circumferential connection (ablation along 90% to 100%) in 29 (14%) PVs. Circumferential LA-PV connections were more common in superior than in inferior PVs (20% versus 7%, P P P Conclusions— The extent of LA-PV connections corresponds with arrhythmognesis. The incidence of PV firing increases with progressively wider LA-PV connections (discrete versus broad versus circumferential).