Abstract
Background The inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischemia, poor functional outcome, and case-fatality. In experimental SAH studies, complement C5 antibodies administered shortly after SAH reduced brain injury with approximately 40%. Complement component C5 may be a new therapeutic target to reduce brain injury and hereby improve outcome after aSAH. We aim to investigate the pharmacodynamic efficacy and safety of eculizumab (complement C5 antibody) in patients with aSAH.
Methods A randomized, controlled, open-label, phase II clinical trial with blinded outcome assessment. Eculizumab (1200 mg) is administered intravenously <12 hours, on day 3 and on day 7 after ictus. Patients in the intervention group receive prophylactic antibiotics for 4 weeks, and those with a central line or an external ventricular shunt and a positive fungal or yeast culture also receive prophylactic antifungal therapy for 4 weeks. The primary outcome is C5a concentration in cerebrospinal fluid (CSF) on day 3 after ictus. Secondary outcomes include the occurrence of adverse events, inflammatory parameters in blood and CSF, cerebral infarction on magnetic resonance imaging, and clinical- and cognitive outcomes. We aim to evaluate 26 patients with CSF assessments, 13 in the intervention group and 13 in the comparator group. To compensate for early case-fatality and inability to obtain CSF, we will include 20 patients per group.
Discussion The CLASH trial is the first trial to investigate the pharmacodynamic efficacy and safety of eculizumab in the early phase after aSAH.
Trial registration Netherlands Trial Register: NTR6752, https://www.trialregister.nl/trial/6579. Registered on 27 October 2017. European Clinical Trials Database: EudraCT 2017-004307-51.
Benefits and Sustainability of a Learning Collaborative for Implementation of Treat-to-Target in Rheumatoid Arthritis: Results of a Cluster-Randomized Controlled Phase II Clinical Trial