A randomised-controlled Phase I de-escalation trial of Molnupiravir and Nirmatrelvir/Ritonavir combination for mild-moderate SARS-CoV-2 infection

BackgroundThe 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. MethodsAdult 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. FindingsOf 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. InterpretationMolnupiravir in combination with nirmatrelvir/ritonavir was safe and well-tolerated; later phase trials should evaluate combination therapy at currently recommended doses for each drug. Research in Context Evidence before this studySARS-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 (26th 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. Added value of this studyCoadministration 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. Implications of all the available evidenceMolnupiravir 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.