{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T21:51:03Z","timestamp":1779313863740,"version":"3.51.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Randomized controlled trial data for non-histaminergic normal C1 inhibitor (nC1INH) angioedema prevention are lacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients aged \u226512 years with investigator-confirmed non-histaminergic nC1INH angioedema were enrolled in phase III, multicenter, randomized, placebo-controlled, double-blind CASPIAN Study (NCT04206605). Patients with \u22651 investigator-confirmed angioedema attack\/4 weeks during observation period were randomized 2:1 to lanadelumab 300 mg every 2 weeks or placebo. Primary efficacy outcome was investigator-confirmed angioedema attack number during the 26-week treatment period. Safety was analyzed as treatment-emergent adverse events (TEAEs). After completing the treatment period, patients could roll over to CASPIAN open-label extension (CASPIAN OLE; NCT04444895) for an additional 26-week lanadelumab treatment to assess long-term safety and efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 77 patients (mean \u00b1 SD age of 42.8 \u00b1 12.9 years, 80.5% women, 88.3% White) were enrolled (lanadelumab, 50; placebo, 27). Primary efficacy outcome was not different with lanadelumab versus placebo (1.82 vs. 1.78 attacks\/month; rate ratio, 1.02; p=0.90), with attack rate reduction from baseline in both groups. Subgroups meeting a clinical definition of HAE [known mutations (n=5) or family history and unknown mutations (n=13)] showed positive attack rate reduction trend with lanadelumab versus placebo. Angioedema attack rate reduction with lanadelumab was observed in CASPIAN OLE. In both studies, all treatment-related TEAEs were non-serious, and most were non-severe; most frequent treatment-related TEAEs were similar to those previously reported in lanadelumab clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In patients with non-histaminergic nC1INH angioedema, lanadelumab safety was consistent with previous studies; efficacy remained inconclusive due to unmet CASPIAN primary endpoint. Overall results suggest potential clinical benefit in symptom control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:uri>https:\/\/www.clinicaltrials.gov\/<\/jats:uri>, identifiers NCT04206605, NCT04444895.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1502325","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T14:39:57Z","timestamp":1747838397000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Lanadelumab for prevention of attacks of non-histaminergic normal C1 inhibitor angioedema: results from the randomized, double-blind CASPIAN Study and CASPIAN open-label extension"],"prefix":"10.3389","volume":"16","author":[{"given":"Marc 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