Diverse Trial Designs, Populations, and Outcomes: A Systematic Literature Review of Trials for the Treatment of Hereditary Angioedema Attacks

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disorder affecting approximately 1 in 50,000 people. As of July 2025, five on-demand treatments for HAE attacks have been approved based on phase 2/3 and phase 3 randomized clinical trials (RCTs). This systematic literature review (SLR) aimed to evaluate clinical trial designs, populations, and outcomes to better understand factors influencing observed treatment effects. METHODS: Following health technology assessment methodology and standards, a comprehensive SLR was conducted through October 2024 using MEDLINE, MEDLINE In-Process, Embase, and the Cochrane Library. Eligible studies were phase 2-3 RCTs evaluating ecallantide, icatibant, plasma-derived C1 esterase inhibitor (C1-INH), recombinant human C1-INH (rhC1-INH), or sebetralstat, and reporting efficacy (e.g., time to onset of symptom relief [TOSR] or time to complete resolution [TTCR]). Assessments included trial design, attack characteristics, and patient-reported outcome (PRO) measures. RESULTS: Of the 12 RCTs evaluated, 11 were center-based and 1 was home-based with e-diary collection. Center-based trials required presentation within 5-8 h after attack onset, whereas the home-based trial instructed immediate treatment, resulting in faster treatment times (median, 215-630 min vs. 35-51 min, respectively). Baseline attack severity was a key differentiator between trials, with some trials requiring a minimum severity of ≥ 30 mm or ≥ 50 mm on the visual analog scale. Censoring criteria differed in timing and conditions (e.g., rescue medication, redosing), with placebo arm censoring rates exceeding 50% in some trials. Eight trials used TOSR as the primary endpoint, measured by six distinct PRO instruments with variable definitions of improvement and success. CONCLUSION: Substantial heterogeneity in trial design, attack eligibility criteria, redosing and rescue protocols, censoring rules, and endpoint definitions limit cross-trial comparability of on-demand HAE therapies. Future comparative efficacy research should prioritize harmonization of endpoint definitions, map across PRO instruments, and adjust for treatment effect modifiers.