In both groups, 99% of pts who had no BTH during wks 0-26 experienced no BTH incidents during wks 27-52. RESULTS: Study 301: 243 pts entered the extension period (R-R arm: n=124 E-R arm: n=119). BTH causation was determined by clinical review and categorized as related to inadequate C5 inhibition (free C5 ≥0.5 μg/mL), CAC due to an inciting event (eg, infection, trauma, surgery), or unrelated to either event. The outcome of interest was the proportion of pts with BTH during the extensions of 301 and 302 (wks 27-52), causes, and clinical parameters associated with BTH incidents. ![]() Pts received weight-based dosing of ravulizumab q8w or the approved eculizumab dose (900 mg q2w) for 183 d in the extension, eligible pts continued (R-R arm) or switched to ravulizumab (E-R arm). Pts in study 302 were stable receiving eculizumab treatment for ≥6 mo, with LDH of ≤1.5 × ULN at screening. Pts in study 301 were naive to C5 inhibitor therapy, with LDH of ≥1.5 × ULN and ≥1 sign/symptom of PNH at screening. Eligible pts were ≥18 y with confirmed PNH diagnosis. METHODS: The trials were phase 3, randomized, open-label, noninferiority, multicenter studies. In the current analysis, pt-level data were evaluated to assess causes and clinical parameters associated with BTH incidences reported up to 1 y in the two phase 3 trials. Each study had a 26-wk randomized primary evaluation period, followed by an extension period during which pts could receive ravulizumab for up to 2 y. ![]() In two phase 3 trials, ALXN1210-PNH-301 (301 NCT02946463) and ALXN1210-PNH-302 (302 NCT03056040), ravulizumab (q8w) was shown to be noninferior to eculizumab 900 mg (q2w) for all primary and key secondary endpoints (including BTH). Although there is no broad consensus regarding the definition of BTH, this study defined BTH based on literature review and expert consensus: ≥1 new or worsening sign or symptom of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular event, dysphagia, or erectile dysfunction) in the presence of elevated lactate dehydrogenase (LDH) (≥2 × ULN) after prior LDH reduction to Ravulizumab, an innovative long-acting C5 complement inhibitor, was recently approved in the United States, Japan, and Europe for the treatment of PNH. BTH may be associated with inadequate C5 inhibition or complement-activating conditions (CACs eg, infection). INTRODUCTION: In patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) receiving eculizumab, approximately 11%-27% may experience breakthrough hemolysis (BTH)-the return of hemolytic disease activity.
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