One year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study (preprint)

BackgroundIn patients with COVID-19 requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) one year after discharge. MethodsAdults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies. HRQoL, assessed by EQ-5D-5L utility index, pre-hospital and one year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. FindingsIn 1,888 participants included in the primary analysis, 1,149 received corticosteroids. There was no between-group difference in EQ-5D-5L utility index at one year (mean difference 0.004, 95% CI: -0.026 to 0.034, p = 0.77). A similar reduction in EQ-5D-5L was seen at one year between corticosteroid exposed and non-exposed groups (mean (SD) change -0.12 (0.22) vs -0.11 (0.22), p = 0.32). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a larger cohort of 109,318 patients admitted to hospital with COVID-19, EQ-5D-5L utility index at one year remained similar between the two groups. InterpretationSystemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL one year after hospital discharge. Treatments to address this are urgently needed. Take home messageSystemic corticosteroids given for acute COVID-19 do not affect health-related quality of life or other patient reported outcomes, physical and mental health outcomes, and organ function one year after hospital discharge

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease (preprint)

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Cohort Profile: Post-hospitalisation COVID-19 study (PHOSP-COVID) (preprint)

Abstract [bullet] PHOSP-COVID is a national UK multi-centre cohort study of patients who were hospitalised for COVID-19 and subsequently discharged. [bullet] PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalisation, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments, and to serve as a platform to enable future studies, including clinical trials. [bullet] Data collected covered a wide range of physical measures, biological samples, and Patient Reported Outcome Measures (PROMs). [bullet] Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA, or in Tier 2 where they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at five (range 2-7) months and 12 (range 10-14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites. [bullet] All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research. [bullet] In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022. [bullet] Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals.

A Randomised -Controlled Phase 2 trial of Molnupiravir in Unvaccinated and Vaccinated Individuals with Early SARS-CoV-2 (preprint)

Background Molnupiravir 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. Methods Adult 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. Findings Of 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=1.30, 95% CrI 0.92-1.71, p=0.7 by Logrank and p=0.03 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 75.4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94.7%. 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. Interpretation We 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.

Characterisation of SARS-CoV-2 genomic variations in response to molnupiravir treatment in the AGILE Phase IIa clinical trial. (preprint)

Molnupiravir is an antiviral approved for treating COVID-19, which is thought to drive lethal error catastrophe. How this drug-induced mechanism of action impacts the emergence of resistance mutations is unclear. AGILE Candidate Specific Trial (CST)-2 is a phase IIa trial randomising 180 adult outpatients with SARS-COV-2 infection within five days of symptom onset to molnupiravir or placebo, with rich serial sampling of nasopharyngeal swabs over 29 days. Viral sequences, that passed genome quality control criteria, from subjects who received molnupiravir (n=59) or a placebo (n=65) were analysed by high-throughput amplicon sequencing. We found evidence that molnupiravir significantly increased the transition/transversion frequency in SARS-CoV-2 in patients, a hallmark of molnupiravir treatment. Over the course of treatment, no consistent, accumulated mutations were identified in either arm.

Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study (preprint)

Background There 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. Methods PHOSP-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. Findings 2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35.6% were female, mean age 58.7 (SD 12.5) years, and 27.8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/165 (25.6%) and one year 232/804 (28.9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0.68 (95% CI 0.46-0.99), obesity OR 0.50 (95%CI 0.34-0.74) and IMV OR 0.42 (95%CI 0.23-0.76). 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) 0.88 (0.74-1.00), five months 0.74 (0.60-0.88) to one year: 0.74 (0.59-0.88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. Interpretation The 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.

Pharmacokinetics of β-d-N4-hydroxycytidine, the active metabolite of prodrug molnupiravir, in non-plasma compartments of patients with SARS-CoV-2 infection (preprint)

BackgroundMolnupiravir, an orally administered prodrug of the broadly active, direct-acting antiviral, ribonucleoside analogue {beta}-d-N4-hydroxycytidine (NHC) is a promising COVID-19 drug candidate. We characterised the pharmacokinetics of NHC in saliva, nasal secretions and tears of patients enrolled in the phase I AGILE trial (NCT04746183) to understand its potential in preventing infection and transmission. MethodsPatients with PCR-confirmed SARS-CoV-2 infection, within 5 days of symptom onset with mild-to-moderate disease were randomised to oral molnupiravir 300, 600 or 800 mg twice daily or placebo. Plasma and non-plasma (saliva, nasal secretions and tears) samples were collected at pre-dose, 0.5, 1, 2, and 4 hours post-dose on study days 1 and 5 and molnupiravir and NHC measured by LC/MS with a lower limit of quantification of 2.5 ng/mL in all matrices. Pharmacokinetic parameters were determined by noncompartmental methods and non-plasma:plasma ratios (RNP:P; based on AUC0-4) calculated. ResultsTwelve participants (n=4 per dosing arm; 75% female) completed the study. NHC Tmax ranged between 1.00-4.00 hours for saliva (n=21) and nasal swabs (n=22) and 0.50-4.00 hours (n=17) for tears compared to 1.00-2.00 hours for plasma (n=19). Median (range) saliva RNP:P pooled across doses was 0.03 (0.01-0.11); n=16. RNP:P for nasal secretions and tears were 0.21 (0.05-0.73); n=17 and 0.22 (0.09-1.05); n=12, respectively. Non-plasma and plasma concentrations were significantly correlated (p<0.0001). ConclusionThese data provide encouraging information regarding the distribution of NHC at sites of viral transmission and have important implications for prophylactic coverage.

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase 1, dose-escalating, randomised controlled study (preprint)

Background AGILE 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. Methods We 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. Results Of 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%. Conclusion Molnupiravir was safe and well tolerated; a dose of 800mg twice-daily for 5 days was recommended for Phase II evaluation.