Results
dysgeusia, fever
VIRUS, ADVERSE EVENTS, DISEASE, RECRUITMENT, TRANSITION MUTATION
The platform trial began recruitment on Sept 30, 2021. The molnupiravir and ritonavir-boosted nirmatrelvir groups started enrolment on June 6, 2022, when both drugs became available in Thailand. Initially, the prespecified interim analyses compared each drug individually with the concurrent no study drug group. By the fifth interim analysis (Aug 22, 2022, using data from 12 patients randomly assigned to ritonavir-boosted nirmatrelvir and 20 concurrent controls), ritonavir-boosted nirmatrelvir had met the stopping rule for success (probability >0·9 that viral clearance was increased by >12·5%). As a result, ritonavir-boosted nirmatrelvir remained in the platform trial but then became the positive control. Molnupiravir met the stopping rule for success at the sixth interim analysis (Oct 19, 2022; 28 patients had been randomly assigned to molnupiravir with 37 concurrent controls). Molnupiravir stayed in the trial, but then entered a non-inferiority comparison with ritonavir-boosted nirmatrelvir (In the modified intention-to-treat population there were 3704 qPCR viral density measurements (a median of 18 viral load estimates per patient [IQR 18–18] over 8 days) of which 2977 (80%) were above the lower limit of quantification. The median baseline oropharyngeal sample viral density was 10Median estimated viral clearance half-lives under the linear model were 8·5 h (IQR 6·7–10·1) with ritonavir-boosted nirmatrelvir, 11·6 h (8·6–15·4) with molnupiravir, and 15·5 h (11·9–21·2) in the contemporaneous no study drug group. Median virus clearance half-life was nearly halved by ritonavir-boosted nirmatrelvir and reduced by one third by molnupiravir, compared with no study drug (No patients developed severe disease or were hospitalised. There were no significant differences in fever clearance across the three intervention groups (although power was low as only a third of patients had fever at baseline; In an exploratory analysis, a higher proportion of patients had viral rebound in the ritonavir-boosted nirmatrelvir group (six [10%] of 58) compared with the molnupiravir group (one [2%] of 65; p=0·051) or the no study drug group (one [1%] of 84; p=0·018; The oropharyngeal swabbing procedure and all treatments were well tolerated. Patients receiving ritonavir-boosted nirmatrelvir commonly complained of dysgeusia but none discontinued treatment as a result. There were no treatment-related serious adverse events (To compare antiviral effects of all the unmasked small molecule drugs tested in the PLATCOV platform trial, we performed an individual patient data meta-analysis using patients recruited to the same centre in Thailand. This comprised recipients of ivermectin,61 samples (1–6 per individual) taken on day 7 or later from 31 individuals with persistent oropharyngeal swab cycle threshold values less than 35, were sequenced successfully. Three of these individuals received ritonavir-boosted nirmatrelvir, nine received molnupiravir, and 19 received no study drug. All baseline isolates were also sequenced. An increased number of single nucleotide polymorphisms (SNPs) relative to baseline was found in three of the nine molnupiravir isolates from day 7 or later and none in the ritonavir-boosted nirmatrelvir or no study drug samples (Among these three isolates, there were three branches containing ten or more SNPs. A previously identified mutational signature associated with molnupiravir is characterised by excess transition mutations which are mainly C to T and G to A mutations.A search of publicly available genome databases did not find any evidence of onward transmission of these strains. Using public datasets on predicted fitness effects of amino acid mutations there were a small number of mutations with elevated predicted fitness, but all three strains scored lower than the parent day 0 strain (