TY - JOUR
T1 - Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH)
T2 - A phase 2a randomized clinical trial
AU - Koopman, Inez
AU - Tack, Reinier Wp
AU - Wunderink, Herman F
AU - Bruns, Anke Hw
AU - van der Schaaf, Irene C
AU - Cianci, Daniela
AU - Gelderman, Kyra A
AU - van de Ridder, Inge M
AU - Hol, Elly M
AU - Rinkel, Gabriel Je
AU - Vergouwen, Mervyn DI
N1 - 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.
PY - 2023/12
Y1 - 2023/12
N2 - 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 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/.
AB - 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 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/.
KW - complement
KW - inflammation
KW - safety and efficacy
KW - Subarachnoid hemorrhage
UR - http://www.scopus.com/inward/record.url?scp=85168895892&partnerID=8YFLogxK
U2 - 10.1177/23969873231194123
DO - 10.1177/23969873231194123
M3 - Article
C2 - 37606053
SN - 2396-9873
VL - 8
SP - 1097
EP - 1106
JO - European Stroke Journal
JF - European Stroke Journal
IS - 4
ER -