Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was 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. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that 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 Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.

Public Engagement with Science via Social Media: A Case of Communicating the Pandemic on Twitter.

The poster describes a project which analyzes interactions between laypeople and experts via social media. Our aim is to understand how experts and the general public interact with each other on social media, and how we can use current data to improve these interactions in the future. We created a Twitter bot to obtain data from 15 COVID-19 experts and 7 federal government-sponsored public health organizations from English-speaking countries. The data were analyzed in R to investigate the relationships among Followers, Favorites, Retweets, and Hashtag Count per tweet. The preliminary analysis indicated statistically significant differences between various variables including: Number of Favorites, Number of Retweets, Number of Hashtags, and Number of Followers; the results shed light on the current relationship between the public and experts on social media.

The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. FINDINGS: Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). INTERPRETATION: Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Specific language impairment and school outcomes. II: Educational context, student satisfaction, and post-compulsory progress.

BACKGROUND: This investigation is the second paper of a companion set reporting the outcomes of secondary schooling for young people who have been participating in the Manchester Language Study. AIMS: To examine the school context of educational results at 16 years of age and to provide information on the adolescents' post-16 activities. METHODS & PROCEDURES: A total of 120 adolescents with a history of specific language impairment (SLI) and 121 adolescents with typical development (TD) in their final year of compulsory secondary schooling (mean age = 17;4 years) participated in the study. Data on educational placement, special education support and provision of statement of special educational needs (SEN) were collected, along with the provision of access arrangements during examinations. Adolescents were interviewed about their levels of expectation and satisfaction with their examination results and their subsequent post-16 activities. OUTCOMES & RESULTS: Only a small proportion of adolescents attended special units/schools throughout their secondary schooling; a larger proportion consistently attended mainstream schools. Those in receipt of a statement of SEN performed more poorly in their examinations than those without a statement. Around 60% of the adolescents with SLI were provided with some type of access arrangements during their core examinations. The majority (88%) of adolescents with SLI reported that they were satisfied with their educational outcomes. Most adolescents with SLI (91%), regardless of school placement at 16 years, remained in education post-16, with the majority in college settings. CONCLUSIONS: Adolescents with a history of SLI have continued difficulties throughout secondary schooling, with three-quarters of the sample receiving some form of special education in a variety of settings. Educational attainment varied across different groups of adolescents but was consistently poorer than the attainment of typically developing peers. Young people with SLI in the 2000s appear to have more opportunities to remain in education post-16 than they did in the 1990s.

Specific language impairment and school outcomes. I: identifying and explaining variability at the end of compulsory education.

BACKGROUND: This investigation reports the results of national educational examinations in secondary schooling for young people who have been participating in the Manchester Language Study. AIMS: The emphasis of the study is on furthering understanding of educational outcomes at the end of compulsory education. METHODS & PROCEDURES: A total of 120 adolescents with a history of specific language impairment (SLI) and 121 adolescents with typical development (TD) who were in their final year of compulsory secondary schooling (mean age = 17;4 years) participated. National educational examination results throughout secondary schooling were collected along with a range of psycholinguistic skills from 11 to 16/17 years. OUTCOMES & RESULTS: Forty-four per cent of young people with SLI obtained at least one of the expected qualifications at the end of secondary education, indicating some improvements compared with reports on earlier cohorts. Regression analyses revealed that literacy and language skills were predictive of educational attainment after controlling for IQ and maternal education. Nearly one-quarter of the sample of adolescents with SLI was not entered for any examinations at the end of compulsory education. A very strong association between earlier patterns of entry for examinations and patterns of examination entry at school leaving age was found. CONCLUSIONS: In addition to performance IQ, concurrent and early literacy and language skills have significant effects on the academic attainments of young people with a history of SLI. The transition from primary to secondary schooling is a crucial time for assessment and evaluation of individual children's needs and levels of support required.

Bullying risks of 11-year-old children with specific language impairment (SLI): does school placement matter?

In addressing an issue rarely explored in research literature, the prevalence and severity of the risk of being bullied at school was measured in 100 children with specific language impairment (SLI). Participants attended a range of different educational placement types and these were compared for bullying risk. Furthermore, the risk encountered by children with SLI was compared with that of normally developing age-matched peers. Each participant completed a questionnaire and it was found that 36% of participants with SLI considered themselves at risk of being bullied in school compared with only 12% of the normally developing cohort. No statistically significant difference was found between the risk experienced by participants with SLI attending mainstream education and that by participants attending special education placements. Possible explanations for the results are offered and the relevance of the findings in the context of optimizing the educational experience of children with SLI is highlighted.

Different school placements following language unit attendance: which factors affect language outcome?

The study compared the outcomes of two groups of children who were attending language unit provision at 7 years of age. Of 242 children in the original study, 62 (28%) transferred to mainstream school placements at age 8 years. These children were then closely matched to children still attending language unit provision at this age using measures of non-verbal IQ, expression and comprehension. These two groups of children were compared on outcome at 11 years in the areas of language skill, non-verbal IQ and social behaviour. Teacher/speech-language therapist opinions of placement were also examined as factors affecting outcome. Results show that children who moved to mainstream provision at 8 years were more likely to be attending mainstream at 11 years, although the majority received extra support. No further differences were evident in outcome according to placement type. However, there was a main effect of teacher/therapist opinion on outcome--children whose teachers were not entirely happy with the 8-year placement performed more poorly at 11 years on language measures. There were no differences on any other measures. The findings suggest that follow-on placements for children attending language units need to be more closely in line with teacher's opinions and that more flexibility needs to be evident in school placement policy in order that appropriate educational settings can be arranged.