Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. FINDINGS: 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. INTERPRETATION: Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. FUNDING: BioShin Limited. TRANSLATIONS: For the Chinese and Korean translations of the abstract see Supplementary Materials section.

Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19.

Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections.

Regulation of angiotensin-converting enzyme 2 isoforms by type 2 inflammation and viral infection in human airway epithelium.

SARS-CoV-2 enters human cells through its main receptor, angiotensin-converting enzyme 2 (ACE2), which constitutes a limiting factor of infection. Recent findings demonstrating novel ACE2 isoforms implicate that this receptor is regulated in a more complex way than previously anticipated. However, it remains unknown how various inflammatory conditions influence the abundance of these ACE2 variants. Hence, we studied expression of ACE2 messenger RNA (mRNA) and protein isoforms, together with its glycosylation and spatial localization in primary human airway epithelium upon allergic inflammation and viral infection. We found that interleukin-13, the main type 2 cytokine, decreased expression of long ACE2 mRNA and reduced glycosylation of full-length ACE2 protein via alteration of N-linked glycosylation process, limiting its availability on the apical side of ciliated cells. House dust mite allergen did not affect the expression of ACE2. Rhinovirus infection increased short ACE2 mRNA, but it did not influence its protein expression. In addition, by screening other SARS-CoV-2 related host molecules, we found that interleukin-13 and rhinovirus significantly regulated mRNA, but not protein of transmembrane serine protease 2 and neuropilin 1. Regulation of ACE2 and other host proteins was comparable in healthy and asthmatic epithelium, underlining the lack of intrinsic differences but dependence on the inflammatory milieu in the airways.

Telemedicine efficacy and satisfaction of patients and headache specialists in migraine management.

Background: Migraine follow-up is difficult for outpatients, especially after the COVID-19 pandemic, we tried to identify the most appropriate telemedicine methods for migraine in terms of efficacy, safety, patient compliance, and patient and physician satisfaction. Methods: Migraine patients were screened from the Headache Center of the First Affiliated Hospital of Chongqing Medical University from September 2019 to December 2021 and randomly classified into an outpatient group and four telemedicine groups: social software, telephone, E-mail, and short message. Headache specialists followed up with the patients 3 and 6 months after their visit and asked about their satisfaction with the follow-up in each instance, as were the headache specialists. Results: A total of 147 migraine patients were included, of whom 65 completed the follow-up. After 3 and 6 months of follow-up, the proportion of patients whose monthly headache frequency decreased by over 50% in the social-software, telephone, and E-mail groups was no different from that in the outpatient group. A similar result was obtained from evaluations with the Visual Analog Scale, the Headache Impact Test and the Migraine Disability Assessment compared with baseline in social software and telephone groups. The compliance in social-software group was not worse than that in the outpatient group. The proportion of patients in the E-mail group who completed the follow-up and the proportion of patients in the telephone group who consistently took preventive medication were significantly lower than those in the outpatient group. After 6 months, the majority of patients in the outpatient, social-software, and telephone groups and headache specialists in the outpatient, social-software groups were satisfied with the follow-up, while fewer patients in the E-mail group and fewer specialists in the telephone and E-mail group showed their satisfaction. Conclusion: Compared with outpatient visits, it is safe and effective to use social software and telephone to follow up on migraine patients, and E-mail and short-message follow-up have lower feasibility. Migraine patients prefer social-software and telephone follow-up, while specialists prefer social-software follow-up.

Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.

BACKGROUND: Coronavirus disease-2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID-19 may impact the development of the MDR. METHODS: Blood and skin samples from COVID-19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID-MDR), healthy controls, non-COVID-19-related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high-throughput multiplexed proteomic profiling of serum were performed. RESULTS: IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8+ T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID-MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID-MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID-MDR patients revealed upregulation of various inflammatory mediators (IL-4, IL-5, IL-6, TNF, and IFN-γ), eosinophil and Mo/Mac -attracting chemokines (MCP-2, MCP-3, MCP-4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID-MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features. CONCLUSION: A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8+ T cells in severe COVID-19 patients, which in turn may impact the development of MDR.

Clinical, radiological, and laboratory characteristics and risk factors for severity and mortality of 289 hospitalized COVID-19 patients.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a global pandemic, with 10%-20% of severe cases and over 508 000 deaths worldwide. OBJECTIVE: This study aims to address the risk factors associated with the severity of COVID-19 patients and the mortality of severe patients. METHODS: 289 hospitalized laboratory-confirmed COVID-19 patients were included in this study. Electronic medical records, including patient demographics, clinical manifestation, comorbidities, laboratory tests results, and radiological materials, were collected and analyzed. According to the severity and outcomes of the patients, they were divided into three groups: nonsurvived (n = 49), survived severe (n = 78), and nonsevere (n = 162) groups. Clinical, laboratory, and radiological data were compared among these groups. Principal component analysis (PCA) was applied to reduce the dimensionality and visualize the patients on a low-dimensional space. Correlations between clinical, radiological, and laboratory parameters were investigated. Univariate and multivariate logistic regression methods were used to determine the risk factors associated with mortality in severe patients. Longitudinal changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay were also collected. RESULTS: Of the 289 patients, the median age was 57 years (range, 22-88) and 155 (53.4%) patients were male. As of the final follow-up date of this study, 240 (83.0%) patients were discharged from the hospital and 49 (17.0%) patients died. Elder age, underlying comorbidities, and increased laboratory variables, such as leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) on admission, were found in survived severe cases compared to nonsevere cases. According to the multivariate logistic regression analysis, elder age, a higher number of affected lobes, elevated CRP levels on admission, increased prevalence of chest tightness/dyspnea, and smoking history were independent risk factors for death of severe patients. A trajectory in PCA was observed from "nonsevere" toward "nonsurvived" via "severe and survived" patients. Strong correlations between the age of patients, the affected lobe numbers, and laboratory variables were identified. Dynamic changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay showed that continuing increase of leukocytes and neutrophil count, sustained lymphopenia and eosinopenia, progressing decrease in platelet count, as well as high levels of NLR, CRP, PCT, AST, BUN, and serum creatinine were associated with in-hospital death. CONCLUSIONS: Survived severe and nonsurvived COVID-19 patients had distinct clinical and laboratory characteristics, which were separated by principle component analysis. Elder age, increased number of affected lobes, higher levels of serum CRP, chest tightness/dyspnea, and smoking history were risk factors for mortality of severe COVID-19 patients. Longitudinal changes of laboratory findings may be helpful in predicting disease progression and clinical outcome of severe patients.

Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors.

BACKGROUND: Morbidity and mortality from COVID-19 caused by novel coronavirus SARS-CoV-2 is accelerating worldwide, and novel clinical presentations of COVID-19 are often reported. The range of human cells and tissues targeted by SARS-CoV-2, its potential receptors and associated regulating factors are still largely unknown. The aim of our study was to analyze the expression of known and potential SARS-CoV-2 receptors and related molecules in the extensive collection of primary human cells and tissues from healthy subjects of different age and from patients with risk factors and known comorbidities of COVID-19. METHODS: We performed RNA sequencing and explored available RNA-Seq databases to study gene expression and co-expression of ACE2, CD147 (BSG), and CD26 (DPP4) and their direct and indirect molecular partners in primary human bronchial epithelial cells, bronchial and skin biopsies, bronchoalveolar lavage fluid, whole blood, peripheral blood mononuclear cells (PBMCs), monocytes, neutrophils, DCs, NK cells, ILC1, ILC2, ILC3, CD4+ and CD8+ T cells, B cells, and plasmablasts. We analyzed the material from healthy children and adults, and from adults in relation to their disease or COVID-19 risk factor status. RESULTS: ACE2 and TMPRSS2 were coexpressed at the epithelial sites of the lung and skin, whereas CD147 (BSG), cyclophilins (PPIA andPPIB), CD26 (DPP4), and related molecules were expressed in both epithelium and in immune cells. We also observed a distinct age-related expression profile of these genes in the PBMCs and T cells from healthy children and adults. Asthma, COPD, hypertension, smoking, obesity, and male gender status generally led to the higher expression of ACE2- and CD147-related genes in the bronchial biopsy, BAL, or blood. Additionally, CD147-related genes correlated positively with age and BMI. Interestingly, we also observed higher expression of CD147-related genes in the lesional skin of patients with atopic dermatitis. CONCLUSIONS: Our data suggest different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells. Altered expression of these receptors related to age, gender, obesity and smoking, as well as with the disease status, might contribute to COVID-19 morbidity and severity patterns.