Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH): A phase 2a randomized clinical trial
Inez Koopman, Reinier WP Tack, Herman F Wunderink, Anke HW Bruns, Irene C van der Schaaf, Daniela Cianci, Kyra A Gelderman, Inge M van de Ridder, Elly M Hol, Gabriel JE Rinkel, Mervyn DI Vergouwen- Cardiology and Cardiovascular Medicine
- Neurology (clinical)
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/