BACKGROUND:Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS:In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS:A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS:Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

The absence of validated nonirritant concentrations limits the diagnosis of immediate hypersensitivity reactions to systemic corticosteroids. This work establishes nonirritant concentrations for skin tests with systemic corticosteroids and their main excipients, making them applicable in clinical practice.

Background: Allergy to beta-lactam (beta L) antibiotics is highly reported in children, but rarely confirmed. Risk factors for a positive diagnostic work-up are scarce. The primary aim was to characterize the cases of children with confirmed beta L allergy, investigating potential risk factors. Secondary aims were to assess the prevalence of allergy to beta L in this population and to confirm the safety of less extensive diagnostic protocols for milder reactions. Methods: We reviewed the clinical data from all children evaluated in our Department for suspected beta L allergy, over a six-year period. Results: Two hundred and twenty children (53% females) with a mean age of 6.5 +/- 4.2 years were evaluated. Cutaneous manifestations were the most frequently reported (96.9%), mainly maculopapular exanthema (MPE). The reactions were non-immediate in 59.5% of the cases. Only 23 children (10.5%) were diagnosed with allergy to beta L. The likelihood of beta L allergy was significantly higher in children with a family history of drug allergy (p< 0.001) and in those with a smaller time period between the reaction and the study (p =0.046). The probability of not confirming beta L allergy is greater in children reporting less severe reactions (p< 0.001) and MPE (p< 0.001). We found the less extensive diagnostic protocol in milder reactions safe, since only 4.2% of the children presented a positive provocation test (similar reaction as the index reaction). Conclusion: This study highlights family history of drug allergy as a risk factor for a positive diagnostic work-up. Larger series are required, particularly genetic studies to accurately determine future risk for beta L allergy in children. (C) 2020 SEICAP. Published by Elsevier Espana, S.L.U. All rights reserved.