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

Khoo, Saye ORCID: https://orcid.org/0000-0002-2769-0967, FitzGerald, Richard, Saunders, Geoffrey, Mozgunov, Pavel ORCID: https://orcid.org/0000-0001-6810-0284, Reynolds, Helen ORCID: https://orcid.org/0000-0001-7443-4520, Greenhalf, William ORCID: https://orcid.org/0000-0002-1865-3195, Else, Laura, Hiscox, Julian ORCID: https://orcid.org/0000-0002-6582-0275, Jaki, Thomas ORCID: https://orcid.org/0000-0002-1096-188X, Fletcher, Thomas and Griffiths, Gareth ORCID: https://orcid.org/0000-0002-9579-8021 (2019) AGILE: Candidate specific trial protocol 2 (CST2): EIDD-2801 (molnupiravir) Primary Analysis. [Data Collection]

Description

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. ß-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.

Keywords:	COVID-19, AGILE, antiviral therapy, randomised controlled trial, Molnupiravir
Divisions:	Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology > Pharmacology and Therapeutics
Depositing User:	Helen Reynolds
Date Deposited:	15 Mar 2023 15:09
Last Modified:	21 Dec 2023 14:29
DOI:	10.17638/datacat.liverpool.ac.uk/938
Collection Name:	The AGILE Clinical Trial Platform (COVID-19)
Geography:	United Kingdom
URI:	https://datacat.liverpool.ac.uk/id/eprint/938
Additional details Additional details Creators: Khoo, Saye FitzGerald, Richard Saunders, Geoffrey Mozgunov, Pavel Reynolds, Helen Greenhalf, William Else, Laura Hiscox, Julian Jaki, Thomas Fletcher, Thomas Griffiths, Gareth Research funder: Grant Number Name of the Funder The Funder's ID Ridgeback Biotherapeutics MR/V028391/1 Medical Research Council MR/M017443/1 221590/Z/20/Z Wellcome Trust 221590/Z/20/Z Date: 8 August 2019 Statement on legal, ethical and access issues : Users are free to access the files within this record according to the licence. The risk of disclosing participants' identities has been mitigated by removing references to names and other identifying information. A unique study ID has been used. Data processing and preparation activities : These data were used for the trial primary analysis detailed in the associated publications. Additional information: Additional data are available in a separate record. Additional associated published papers: Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. https://doi.org/10.1093/jac/dkab318 The development and validation of a novel LC-MS/MS method for the simultaneous quantification of Molnupiravir and its metabolite ß-d-N4-hydroxycytidine in human plasma and saliva. https://doi.org/10.1016/j.jpba.2021.114356 Pharmacokinetics of ß-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection. https://doi.org/10.1093/cid/ciac199 Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial. https://doi.org/10.1038/s41467-022-34839-9 Resource language: English Project Details: Project ID The title of the Project Project Funding ID Project Start Date Project End Date 167430 Assessing druGs for COVID19 In early cLinical phase Expeditiously 168356 16 June 2020 167430 Assessing druGs for COVID19 In early cLinical phase Expeditiously 168587 4 January 2021 31 December 2023 167430 AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment 167880 10 January 2020 31 December 2023 Publisher: University of Liverpool Contact email address: livagile@liverpool.ac.uk Last Modified: 21 Dec 2023 14:29

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AGILE CST2_sa ... PK_SPONSOR.xlsx AGILE CST2_sa ... PK_SPONSOR.xlsx AGILE CST2_sa ... PK_SPONSOR.xlsx Visible to: Anyone Content type: Data Description: Summary of PK parameters from saliva, nasal swabs & tears Metadata Revision: 2 Mime-Type: application/vnd.openxmlformats-officedocument.spreadsheetml.sheet License: Creative Commons: Attribution 4.0 File size: 89kB Creative Commons: Attribution 4.0

AGILE Swab ... 10.01.2023.xlsx AGILE Swab ... 10.01.2023.xlsx AGILE Swab ... 10.01.2023.xlsx Visible to: Anyone Content type: Data Description: Viral load data Metadata Revision: 2 Mime-Type: application/vnd.openxmlformats-officedocument.spreadsheetml.sheet License: Creative Commons: Attribution 4.0 File size: 759kB Creative Commons: Attribution 4.0

20230110_AGILE- ... May2022_v1.xlsx 20230110_AGILE- ... May2022_v1.xlsx 20230110_AGILE- ... May2022_v1.xlsx Visible to: Anyone Content type: Data Description: Variant genotyping spreadsheet Metadata Revision: 3 Mime-Type: application/vnd.openxmlformats-officedocument.spreadsheetml.sheet License: Creative Commons: Attribution 4.0 File size: 29kB Creative Commons: Attribution 4.0

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