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.

Factors associated with the severity of COVID-19 outcomes in people with neuromuscular diseases: Data from the International Neuromuscular COVID-19 Registry.

BACKGROUND AND PURPOSE: Clinical outcome information on patients with neuromuscular diseases (NMDs) who have been infected with SARS-CoV-2 is limited. The aim of this study was to determine factors associated with the severity of COVID-19 outcomes in people with NMDs. METHODS: Cases of NMD, of any age, and confirmed/presumptive COVID-19, submitted to the International Neuromuscular COVID-19 Registry up to 31 December 2021, were included. A mutually exclusive ordinal COVID-19 severity scale was defined as follows: (1) no hospitalization; (2) hospitalization without oxygenation; (3) hospitalization with ventilation/oxygenation; and (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs) for severe outcome, adjusting for age, sex, race/ethnicity, NMD, comorbidities, baseline functional status (modified Rankin scale [mRS]), use of immunosuppressive/immunomodulatory medication, and pandemic calendar period. RESULTS: Of 315 patients from 13 countries (mean age 50.3 [±17.7] years, 154 [48.9%] female), 175 (55.5%) were not hospitalized, 27 (8.6%) were hospitalized without supplemental oxygen, 91 (28.9%) were hospitalized with ventilation/supplemental oxygen, and 22 (7%) died. Higher odds of severe COVID-19 outcomes were observed for: age ≥50 years (50-64 years: OR 2.4, 95% confidence interval [CI] 1.33-4.31; >64 years: OR 4.16, 95% CI 2.12-8.15; both vs. <50 years); non-White race/ethnicity (OR 1.81, 95% CI 1.07-3.06; vs. White); mRS moderately severe/severe disability (OR 3.02, 95% CI 1.6-5.69; vs. no/slight/moderate disability); history of respiratory dysfunction (OR 3.16, 95% CI 1.79-5.58); obesity (OR 2.24, 95% CI 1.18-4.25); ≥3 comorbidities (OR 3.2, 95% CI 1.76-5.83; vs. ≤2; if comorbidity count used instead of specific comorbidities); glucocorticoid treatment (OR 2.33, 95% CI 1.14-4.78); and Guillain-Barré syndrome (OR 3.1, 95% CI 1.35-7.13; vs. mitochondrial disease). CONCLUSIONS: Among people with NMDs, there is a differential risk of COVID-19 outcomes according to demographic and clinical characteristics. These findings could be used to develop tailored management strategies and evidence-based recommendations for NMD patients.

COVID-19 infection and vaccination in patients with skeletal muscle channelopathies.

INTRODUCTION/AIMS: Although we have gained insight into coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 since the beginning of the pandemic, our understanding of the consequences for patients with neuromuscular disorders is evolving. In this study we aimed to study the impact of COVID-19 and COVID-19 vaccination on skeletal muscle channelopathies. METHODS: We conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service. RESULTS: Thirty-eight patient responses were received. Six patients had COVID-19 infection leading to exacerbation of their underlying muscle channelopathy. No major complications were reported. Thirty-six patients had received one or two COVID-19 vaccinations and the majority (68%) had no worsening of their underlying channelopathy. Thirty-two percent reported worsening of their usual symptoms of their muscle channelopathy, but all reported recovery to baseline levels. No serious adverse events were reported. DISCUSSION: The overall rates of COVID-19 infection were low in our study and COVID-19 vaccine uptake rates were high. Our results have been useful to inform patients that a subset of patients have reversible worsening of their channelopathy post-COVID-19 vaccination. Our study provides information for giving advice to patients with skeletal muscle channelopathies regarding COVID-19 infection and vaccination.

COVID-19-Related Outcomes in Primary Mitochondrial Diseases: An International Study.

BACKGROUND AND OBJECTIVES: To identify factors associated with severe coronavirus disease 2019 (COVID-19), defined by hospitalization status, in patients with primary mitochondrial diseases (PMDs), thereby enabling future risk stratification and informed management decisions. METHODS: We undertook a cross-sectional, international, registry-based study. Data were extracted from the International Neuromuscular COVID-19 Database and collected between May 1, 2020, and May 31, 2021. The database included subjects with (1) PMD diagnosis (any age), clinically/histopathologically suspected and/or genetically confirmed; and (2) COVID-19 diagnosis classified as "confirmed", "probable", or "suspected" based on World Health Organization definitions. The primary outcome was hospitalization because of COVID-19. We collected demographic information, smoking status, coexisting comorbidities, outcomes after COVID-19 infection, and PMD genotype-phenotype. Baseline status was assessed using the modified Rankin scale (mRS) and the Newcastle Mitochondrial Disease Adult Scale (NMDAS). RESULTS: Seventy-nine subjects with PMDs from 10 countries were included (mean age 41.5 ± 18 years): 25 (32%) were hospitalized, 48 (61%) recovered fully, 28 (35%) improved with sequelae, and 3 (4%) died. Statistically significant differences in hospitalization status were observed in baseline status, including the NMDAS score (p = 0.003) and mRS (p = 0.001), presence of respiratory dysfunction (p < 0.001), neurologic involvement (p = 0.003), and more than 4 comorbidities (p = 0.002). In multivariable analysis, respiratory dysfunction was independently associated with COVID-19 hospitalization (odds ratio, 7.66; 95% CI, 2-28; p = 0.002). DISCUSSION: Respiratory dysfunction is an independent risk factor for severe COVID-19 in PMDs while high disease burden and coexisting comorbidities contribute toward COVID-19-related hospitalization. These findings will enable risk stratification and informed management decisions for this vulnerable population.