ABSTRACT
BackgroundMolnupiravir was licensed for treating high-risk patients with COVID-19 based on data from unvaccinated adults. AGILE CST-2 (NCT04746183) Phase II reports safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals. MethodsAdult out-patients with PCR-confirmed SARS-CoV-2 infection within five days of symptom onset were randomly assigned 1:1 to receive molnupiravir (800mg twice daily for five days) or placebo. The primary outcome was time to swab PCR-negativity, compared using a Bayesian model for estimating the probability of a superior virological response (Hazard Ratio>1) for molnupiravir over placebo. Secondary outcomes included change in viral titre at day 5, safety and tolerability, clinical progression and patient reported outcome measures. We analysed outcomes after the last participant reached day 29. FindingsOf 180 participants randomised (90 molnupiravir, 90 placebo), 50% were vaccinated. Infections with SARS-CoV-2 variants Delta (40%), Alpha (21%), Omicron (21%) and EU1 (16%) were represented. The median time to negative-PCR was 8 versus 11 days for molnupiravir and placebo (HR=1{middle dot}30, 95% CrI 0{middle dot}92-1{middle dot}71, p=0{middle dot}07 by Logrank and p=0{middle dot}03 by Breslow-Gehan tests). Although small numbers precluded subgroup analysis, no obvious differences were observed between vaccinated and unvaccinated participants. Using a two-point prior the probability of molnupiravir being superior to placebo (HR>1) was 75{middle dot}4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94{middle dot}7%. As an exploratory analysis, the change in viral titre on day 5 (end of treatment) was significantly greater with molnupiravir compared with placebo. A total of 4 participants reported severe adverse events (grade 3+), 3 of whom were in the placebo arm. InterpretationWe found molnupiravir to be well-tolerated, with evidence for high probability of antiviral efficacy in a population of vaccinated and unvaccinated individuals infected with a broad range of viral variants. FundingFunded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z).
ABSTRACT
BackgroundThere are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. MethodsPHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35{middle dot}6% were female, mean age 58{middle dot}7 (SD 12{middle dot}5) years, and 27{middle dot}8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/1965 (25{middle dot}5%) and one year 232/804 (28{middle dot}9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0{middle dot}68 (95% CI 0{middle dot}46-0{middle dot}99), obesity OR 0{middle dot}50 (95%CI 0{middle dot}34-0{middle dot}74) and IMV OR 0{middle dot}42 (95%CI 0{middle dot}23-0{middle dot}76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0{middle dot}88 (0{middle dot}74-1{middle dot}00), five months 0{middle dot}74 (0{middle dot}60-0{middle dot}88) to one year: 0{middle dot}74 (0{middle dot}59-0{middle dot}88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. InterpretationThe sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. FundingUKRI & NIHR Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Embase databases for large studies reporting one-year follow-up data for hospitalised COVID-19 patients published between January 1, 2021 and November 7, 2021, without language restrictions. Search terms related to COVID-19, hospitalisation and long-term follow-up were used. A large prospective cohort study from Wuhan, China (n = 1276) showed that 49% of patients reported at least one persistent symptom during a follow-up clinic visit at 12 months post COVID-19; no significant improvement in exercise capacity was observed between six- and 12-month visits. Another two large cohort studies in China (n = 2433) and Spain (n = 1950) with one-year follow-up data from telephone interviews showed that 45% and 81% of patients reported at least one residual COVID-19 symptom, respectively. However, no previous studies have compared the trajectories of COVID-19 recovery in patients classified by different clinical phenotypes, and there are no large studies investigating the relationship between systemic inflammation and ongoing health impairments post COVID-19. Added value of this studyIn a diverse population of adults post-hospital admission with COVID-19, our large UK prospective multi-centre study reports several novel findings: the minority felt fully recovered at one year with minimal recovery from five months across any health domain; female sex and obesity are associated with being less likely to feel fully recovered at one year; several inflammatory mediators were increased in individuals with the most severe physical, mental health, and cognitive impairments compared to individuals with milder ongoing impairments. Implications of all the available evidenceBoth pharmacological and non-pharmacological interventions are urgently needed to improve the ongoing burden following hospitalisation for COVID-19 both for individuals and healthcare systems; our findings support the use of a precision medicine approach with potential treatable traits of systemic inflammation and obesity.
ABSTRACT
{beta}-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at sites of SARS-CoV-2 transmission in twelve patients enrolled in AGILE CST-2 (NCT04746183). Saliva, nasal and tear concentrations were 3, 21 and 22% that of plasma. Saliva and nasal NHC concentrations were significantly correlated with plasma (p<0.0001).
ABSTRACT
BackgroundAGILE is a phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. MethodsWe undertook a dose-escalating, open-label, randomised-controlled (standard-of-care) Bayesian adaptive phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomised 2:1 in groups of 6 participants to 300mg, 600mg and 800mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was higher than 25%. Secondary outcomes included safety, clinical progression, pharmacokinetics and virologic responses. ResultsOf 103 volunteers screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 400, 600 or 800mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800mg molnupiravir respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild ([≤]grade 2). The probability of [≥]30% excess toxicity over controls at 800mg was estimated at 0.9%. ConclusionMolnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.
