BACKGROUND: People with hereditary angioedema (HAE) experience anxiety from the unpredictable nature of attacks and the burden of parenteral on-demand therapies, potentially leading to delays or avoidance of treatment. This analysis assessed factors associated with anxiety during attacks and the impact of oral sebetralstat versus placebo on anxiety in the KONFIDENT trial. METHODS: Participants in the randomised, double-blind, phase 3 KONFIDENT trial (NCT05259917) treated attacks with sebetralstat 300 mg, 600 mg or placebo as early as possible after onset. Anxiety was recorded at treatment administration, every 0.5 h thereafter through 4 h, hourly from 5 to 12 h and every 2 h from 14 to 24 h using an 11-point modified General Anxiety Numeric Rating Scale (GA-NRS). Prespecified exploratory endpoints assessed in all attacks and in attacks rated as inducing moderate-to-extreme anxiety (GA-NRS ≥ 4) included cumulative GA-NRS score and meaningful reduction in anxiety (defined as ≥ 2-point reduction in GA-NRS for ≥ 2 consecutive timepoints); least squares mean change from treatment administration in GA-NRS at 4 and 12 h was also assessed. This study was sponsored by KalVista Pharmaceuticals. RESULTS: Overall, 115 (44%) attacks were rated as inducing moderate-to-extreme anxiety. Female sex, shorter time since HAE diagnosis and greater attack severity were associated with greater anxiety at treatment administration. Reduction in cumulative anxiety after sebetralstat use was significantly greater versus placebo. The time to meaningful reduction in anxiety endpoint showed agreement with time to beginning of symptom relief, reduction in attack severity and complete attack resolution endpoints. CONCLUSION: Moderate-to-extreme anxiety was common in HAE attacks. Reduction in anxiety was significantly greater in attacks treated with sebetralstat compared with placebo.