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Introduction <p>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&#xa0;2/3 and phase&#xa0;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.</p> Methods <p>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&#xa0;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.</p> Results <p>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&#xa0;h after attack onset, whereas the home-based trial instructed immediate treatment, resulting in faster treatment times (median, 215–630&#xa0;min vs. 35–51&#xa0;min, respectively). Baseline attack severity was a key differentiator between trials, with some trials requiring a minimum severity of ≥ 30&#xa0;mm or ≥ 50&#xa0;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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Raffi Tachdjian,
  • Nihal Narsipur,
  • Paranjoy Saharia,
  • Sakshi Jindal,
  • Nami Park,
  • Joseph R. Harper,
  • Anurag Relan,
  • John Anderson,
  • Amanda Harrington

摘要

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.