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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 par- ticipants 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 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 of9.27 hours (interquartile range, 1.53 to >12), Z75 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°/o with the 300-mg dose, 49.5% with the 600-mg dose, and 274% 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. [ABSTRACT FROM AUTHOR]

Thomas Wilke,1 Nils Picker,2 Sabrina Mueller,2 Silke Geier,3 Johannes Foersch,4 Jens Aberle,5 Stephan Martin,6 Matthias Riedl,7 Maximilian Gabler31IPAM, University of Wismar 23966 Wismar, Germany; 2Real-World Evidence and Health Economics, Ingress-Health HWM GmbH, Wismar 23966, Germany; 3HP Country Commercial - Market Access, Boehringer Ingelheim Pharma GmbH & Co. Kg, Ingelheim Am Rhein 55216, Germany; 4HP Country Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. Kg, Ingelheim Am Rhein 55216, Germany; 5Department of Internal Medicine III, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg 20246, Germany; 6German Diabetes Center, Leibniz Institute at Heinrich Heine University, Düsseldorf 40591, Germany; 7Center for Diabetology, Internal and Nutritional Medicine, Medicum Hamburg MVZ GmbH, Hamburg 20097, GermanyBackground: A substantial share of type 2 diabetes mellitus (T2DM) patients receive insulin. However, little is known about the real-world treatment patterns around insulin initiation.Methods: This was a retrospective claims data analysis. T2DM patients who initiated an insulin therapy between 01/01/2013 and 31/12/2015 were identified in the German AOK PLUS dataset. For validation of results, additional data on a similar T2DM patient population were collected in a Germany-wide medical chart review.Results: A total of 284,878 T2DM patients were identified. Of these, 27,340 (9.6%) initiated an insulin treatment during the inclusion period (mean age: 72.2 years; 51.4% female). Mean/median weight and BMI of patients with available clinical data was 85.8/84.0 kg (SD:18.9) and 30.6/29.8 kg/m2, (SD:6.1), respectively at baseline. Mean/median HbA1c-value at baseline was 8.4/8.0% (SD: 1.8). Most commonly prescribed antidiabetic drugs (AD) within 6 months before insulin initiation were metformin (MET; 54.0%), DPP-4 inhibitors (DPP-4i; 37.6%), and sulfonylureas (SU; 29.5%). As high as 23.2% of the patients did not receive any AD prescription within 6 months before insulin initiation. A total of 10,953 of above 27,340 insulin starters (40.1%) initiated their insulin therapy without concomitant ADs (insulin monotherapy); 43% of these patients did not receive any AD before insulin initiation. Of the remaining 16,387 patients (59.9%), 4070 patients (14.9%) received MET only as concomitant AD, 6385 (23.4%) received MET plus at least one further AD, and 5932 (21.7%) received at least one further AD excluding MET. Throughout the first year of treatment, prescribed insulin dosage increased over time, resulting in approximately 43.3–77.9 IUs per observed patient day after 12 months of insulin treatment.Conclusions: Characteristics of German T2DM patients initiating insulin deviate substantially from the average German population, especially in terms of weight. We identified an unexpectedly high number of patients without previous AD therapy receiving insulin monotherapy, which is not in line with the clinical guidelines.Keywords: T2DM, antidiabetic treatment, claims data, chart review