Abstract
BackgroundThe inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischaemia, 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 the outcome after aSAH. We aim to investigate the pharmacodynamic efficacy and safety of eculizumab (complement C5 antibody) in patients with aSAH.MethodsA randomised, controlled, open-label, phase II clinical trial with blinded outcome assessment. Eculizumab (1200 mg) is administered intravenously < 12 h, 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 the cerebrospinal fluid (CSF) on day 3 after ictus. Secondary outcomes include the occurrence of adverse events, inflammatory parameters in the 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.DiscussionThe CLASH trial is the first trial to investigate the pharmacodynamic efficacy and safety of eculizumab in the early phase after aSAH.Trial registrationNetherlands Trial Register NTR6752. Registered on 27 October 2017European Clinical Trials Database (EudraCT) 2017-004307-51
Highlights
Background and rationale {6a} Early brain injury and delayed cerebral ischaemia are important determinants of poor outcome after aneurysmal subarachnoid haemorrhage [1]
We found that the C5a concentration in the cerebrospinal fluid (CSF) of aneurysmal subarachnoid haemorrhage (aSAH) patients is highly increased (> 1400 times) compared to the C5a concentration in CSF from patients with unruptured intracranial aneurysms [13]
If the proportion of patients categorized according to the Prognosis on Admission of Aneurysmal Subarachnoid Haemorrhage (PAASH) scale and the median Hijdra score differs between the intervention and comparator groups, a multivariable logistic regression analysis with adjustment for these variables will be performed
Summary
Background and rationale {6a} Early brain injury and delayed cerebral ischaemia are important determinants of poor outcome after aneurysmal subarachnoid haemorrhage (aSAH) [1]. Previous studies found that the complement cascade is activated in patients with SAH and associated with poor functional outcome [7, 8]. C5 antibodies (eculizumab) are already used for other inflammatory diseases such as neuromyelitis optica and myasthenia gravis [14, 15] The aim of this trial is to investigate the pharmacodynamic efficacy (proofof-concept) and safety of eculizumab in patients with aSAH. The inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischaemia, poor functional outcome, and case fatality. We aim to investigate the pharmacodynamic efficacy and safety of eculizumab (complement C5 antibody) in patients with aSAH
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