AGILE: Candidate specific trial protocol 2 (CST2): EIDD-2801 (molnupiravir) Primary Analysis

AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment. (UoL001542B) The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. The randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs, 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. This trial is registered in ClinicalTrials.gov (NCT04746183), and the ISRCTN registry (ISRCTN27106947). We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial to evaluate the safety and optimal dose of molnupiravir in patients with early symptomatic infection. �-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Molnupiravir induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE CST-2. We describe the pre-specified exploratory virological endpoint of CST-2, to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment.