Khoo, Saye 
ORCID: 0000-0002-2769-0967, FitzGerald, Richard, Edwards, Christopher, Ahmad, Shazaad, Saunders, Geoffrey, Else, Laura, Shaw, Victoria ORCID: 0000-0002-0429-0186, Mozgunov, Pavel, Northey, Josh, Dickinson, Laura ORCID: 0000-0001-5557-9396 et al (show 21 more authors)
(2025)
A randomised-controlled Phase I de-escalation trial of Molnupiravir and Nirmatrelvir/Ritonavir combination for mild-moderate SARS-CoV-2 infection
[Preprint]
Abstract
<h4>Summary</h4> <h4>Background</h4> The AGILE CST-8 ( NCT04746183 ) Phase I de-escalation trial evaluated the safety and tolerability of combination molnupiravir and nirmatrelvir/ritonavir for mild-moderate COVID-19. <h4>Methods</h4> Adult out-patients with SARS-CoV-2 infection within five days of symptoms were randomly assigned 2:1 to receive molnupiravir (starting at 800mg twice daily (BD) reducing to 600mg and 400mg if necessary) in combination with nirmatrelvir (300mg)/ritonavir (100mg) BD for 5 days versus Standard of care. Using a dose de-escalation, open-label, Bayesian adaptive Phase I trial a combination dose was considered unsafe if the probability of 30% or greater dose-limiting toxicity risk (DLT - the primary outcome) over standard of care was 25% or higher. Secondary endpoints included tolerability, clinical progression, pharmacokinetics and virological responses. <h4>Findings</h4> Of 49 participants screened, 24 were enrolled (16 combination, 8 standard of care) between January 2023 and September 2023. For the primary endpoint, to day 11, no participant starting molnupiravir at 800mg (BD) in combination with nirmatrelvir/ritonavir reported a DLT by day 11 (primary endpoint) or by day 29; dose de-escalation was not required. No participants reported severe adverse events (grade>=3). Although proportion of swab PCR negativity at day 5 and day 11 were not statistically different, faster initial viral clearance was observed with treatment. Penetration of nirmatrelvir into saliva, nasal secretions and tears was 19%, 65% and 91% that of plasma. <h4>Interpretation</h4> Molnupiravir in combination with nirmatrelvir/ritonavir was safe and well-tolerated; later phase trials should evaluate combination therapy at currently recommended doses for each drug. <h4>Research in Context</h4> <h4>Evidence before this study</h4> SARS-CoV-2 antivirals such as nirmatrelvir/ritonavir, remdesivir and molnupiravir have been associated with clinical benefit and faster viral clearance when given early to patients at high-risk of severe disease. However, evidence has accrued to suggest that virus persists in tissues (e.g. gastrointestinal tract) and in blood even after clearance from the upper respiratory tract. Moreover, persistent viral infection is recognised in individuals who are the most severely immunosuppressed, (e.g. transplant recipients, those with haematological malignancy, or receiving B-cell depleting therapies) suggesting greater antiviral potency is needed. A PubMed search (26 th April 2025) using the terms ‘SARS-CoV-2’ AND ‘antiviral’ AND ‘combination therapy’ revealed descriptions of retrospective and prospective of case series of combination antiviral therapy, usually given to severely immunocompromised patients. Once prospective study from Naples evaluated the monoclonal antibody sotrovimab in combination with antiviral small molecules, without any controls. There were no randomised trials of combination antiviral therapy for SARS-CoV-2, and little recognition that use of agents at their licensed doses might not be be equally safe when combined. <h4>Added value of this study</h4> Coadministration of molnupiravir and nirmatrelvir/ritonavir (at fully licensed doses) is safe and well-tolerated. Although numbers were small and no differences were detectable in time to achieving PCR-negative swabs, we observed a significantly faster rate of initial viral clearance with combination therapy (compared with no antiviral therapy) using a biexponential model to examine the initial ‘fast’ decay in viral elimination. <h4>Implications of all the available evidence</h4> Molnupiravir plus nirmatrelvir/ritonavir represents an oral-based combination regimen for SARS-CoV-2 infection which should be evaluated against conventional monotherapy, particularly in patients with severe immunosuppression. The use of an adaptive Bayesian dose de-escalation design offers advantages in statistical precision and efficient decision-making for combination antiviral therapy.
| Item Type: | Preprint |
|---|---|
| Uncontrolled Keywords: | 32 Biomedical and Clinical Sciences, 3202 Clinical Sciences, Coronaviruses, Clinical Trials and Supportive Activities, Infectious Diseases, Clinical Research, Health Disparities, Emerging Infectious Diseases, Minority Health, Patient Safety, Coronaviruses Therapeutics and Interventions, Health Disparities and Racial or Ethnic Minority Health Research, Biodefense, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Infection, 3 Good Health and Well Being |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences > Clinical Infection, Microbiology & Immunology Faculty of Health & Life Sciences > Clinical Directorate Faculty of Health & Life Sciences > Clinical Directorate > Clinical Directorate Prof Svcs Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > SMIB Professional Services Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Pharmacology & Therapeutics |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 13 Aug 2026 10:28 |
| Last Modified: | 13 Oct 2026 14:35 |
| DOI: | 10.1101/2025.05.01.25326797 |
| Open Access URL: | https://www.medrxiv.org/content/10.1101/2025.05.01... |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3199939 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
Altmetric
Altmetric