Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH): A phase 2a randomized clinical trial
Koopman, Inez; Tack, Reinier Wp; Wunderink, Herman F; Bruns, Anke Hw; van der Schaaf, Irene C; Cianci, Daniela; Gelderman, Kyra A; van de Ridder, Inge M; Hol, Elly M; Rinkel, Gabriel Je; Vergouwen, Mervyn DI
(2023) European Stroke Journal, volume 8, issue 4, pp. 1097 - 1106
(Article)
Abstract
Introduction: Complement C5 antibodies reduce brain injury after experimental subarachnoid hemorrhage. Patients and methods: In this randomized, controlled, open-label, phase 2a clinical trial with blinded-outcome assessment, we included adult aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to a tertiary referral center ⩽11 h after ictus. Patients were randomized (1:1) to eculizumab
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plus care as usual or to care as usual. Eculizumab (1200 mg) was administered <12 h, and on days 3 and 7 after ictus. In the intervention group, all patients received prophylactic antibiotics and, after a protocol amendment, fluconazole if indicated. Primary outcome was C5a concentration in cerebrospinal fluid (CSF) on day 3 after ictus. Safety was monitored during 4 weeks. In each group, 13 patients with CSF assessments were needed to detect a 55% reduction in CSF C5a concentration. Results: From October 2018 to May 2021, we enrolled 31 patients of whom 26 with CSF samples, 13 per group. Median C5a concentration in CSF on day 3 was 251 pg/ml [IQR: 103–402] in the intervention group and 371 pg/ml [IQR: 131–534] in the control group (p = 0.29). Infections occurred in two patients in the intervention group and four patients in the control group. One patient in the intervention group developed a C. albicans meningitis prior to the protocol amendment. Discussion and conclusion: One dose of eculizumab did not result in a ⩾ 55% decrease in C5a concentration in CSF on day 3 after aSAH. The study did not reveal new safety concerns, except for a C. albicans drain-related infection prior to antifungal monitoring and treatment. Trial registration: EudraCT 2017-004307-51, https://www.clinicaltrialsregister.eu/.
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Keywords: complement, inflammation, safety and efficacy, Subarachnoid hemorrhage, Clinical Neurology, Cardiology and Cardiovascular Medicine, Journal Article
ISSN: 2396-9873
Publisher: SAGE Publications Inc.
Note: Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by a combined grant from the Netherlands Organization for Health Research and Development (ZonMw) and the Dutch Brain Foundation (PTO grant 95105015), a ZonMw TOP grant (91217035), and Alexion Pharmaceuticals (ISR grant 100237). Dr. Vergouwen was supported by a Clinical Established Investigator grant by the Dutch Heart Foundation (2018T098). One of the funders of the study, Alexion Pharmaceuticals, was involved in the study design (eculizumab dosing scheme). The funders had no role in data collection, data analysis, data interpretation, or writing of the report. Publisher Copyright: © European Stroke Organisation 2023.
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