Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH): A phase 2a randomized clinical trial.

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/.

Preventable poor outcome from rebleeding by emergency aneurysm occlusion in patients with aneurysmal subarachnoid haemorrhage.

INTRODUCTION: The risk of rebleeding is highest during the initial hours after aneurysmal subarachnoid haemorrhage (aSAH), but the aneurysm is not occluded in all patients immediately after admission.Our aim was to determine the proportion of aSAH patients with poor outcome from early in-hospital rebleeding that can be prevented by three emergency aneurysm occlusion regimes. PATIENTS AND METHODS: From our prospectively collected database, we retrieved from all aSAH patients admitted between July 2007 and July 2017 data on clinical condition on admission, time of rebleeding, and outcome at 3 months. RESULTS: Of 1391 consecutive aSAH patients, 923 were in good clinical condition and had an aneurysm on initial imaging that was amenable for treatment. Poor outcome from rebleeding could have been avoided by treatment <4 h during day time shifts in 4 (0.4% [95% CI: 0.2-1.1]) patients (number needed to treat [NNT]: 250), by treatment and <1 h during daytime shift in 9 (1.0% [95% CI: 0.5-1.8]; NNT: 111), and treatment <1 h at 24/7 basis in 16 (1.7% [95% CI: 1.1-2.8%]; NNT: 59). DISCUSSION: Emergency aneurysm occlusion can reduce poor outcome due to rebleeding, but only in small proportions of patients. Whether such strategies lead to improved outcome for all patients and are cost-effective is highly uncertain. CONCLUSION: We do not recommend instalment of a treatment regimen where occlusion of ruptured aneurysm is performed within 1 h on a 24/7 basis.