Clinical Research Directory

Tocilizumab-aazg for Hemorrhage: Reduction of Ischemic Vascular Events

In this study, tocilizumab-aazg (TYENNE) will be administered to see whether tocilizumab-aazg is safe in patients with a burst brain aneurysm and if it may prevent strokes in patients with a burst brain aneurysm.

Remote Ischemic Conditioning in Aneurysmal SAH

The goal of this clinical trial is to examine the effect of limb occlusion therapy (remote ischemic conditioning, RIC) in subjects with aneurysmal subarachnoid hemorrhage. The main question it aims to answer is whether RIC can improve long-term recovery in participants with aneurysmal subarachnoid hemorrhage. Researchers will compare levels of functional independence in participants in the RIC-group to participants in the sham-group.

Epigenome-wide DNA Methylation Profiling in Aneurysmal Subarachnoid Hemorrhage and Delayed Ischemic Neurologic Deficit

The goal of this observational study is to investigate DNA methylation changes in adults with bleeding from brain aneurysm, which is called aneurysmal subarachnoid hemorrhage (aSAH), and their association with delayed ischemic neurologic deficit (DIND). The main questions it aims to answer are: Are there specific DNA methylation changes in peripheral blood that differentiate patients with aSAH from healthy individuals? Can DNA methylation changes in peripheral blood predict the development of DIND following aSAH? Researchers will compare blood DNA methylation profiles of aSAH patients to healthy controls and also do subgroup analysis of patients with DIND versus those without DIND to see if there are distinct methylation patterns associated with aSAH and DIND. Participants with aSAH will: * Have a blood sample collected shortly after admission to hospital. * Undergo epigenome-wide DNA methylation profiling using the Infinium MethylationEPIC v2.0 BeadChip microarray. * Be monitored for the development of DIND, defined by clinical symptoms and radiographic vasospasm. This study aims to identify potential epigenetic biomarkers for aSAH susceptibility and DIND risk, which could improve early diagnosis and risk stratification in affected patients.

Mechanisms of Brain-Heart Injury of Post-Intracranial Hemorrhage

Intracranial hemorrhage is a condition characterized by high mortality rates and suboptimal functional outcomes. It precipitates both direct brain injury and subsequent secondary injuries, including delayed cerebral ischemia, brain edema, and hydrocephalus. Complications such as cardiac injury may also arise, categorizing them within the cerebrocardiac syndrome (CCS). The clinical spectrum of CCS encompasses acute myocardial injury, acute coronary syndrome, left ventricular systolic and diastolic dysfunction, cardiac arrhythmias, and sudden cardiac death, all of which are associated with increased mortality and deterioration in patient status. The precise pathophysiological mechanisms underlying both cerebral and cardiac injuries remain enigmatic, and the implications for diagnosis and therapeutic strategies are yet to be fully explored. In this study, we propose to enroll patients with intracranial hemorrhage who will undergo conventional treatment and comprehensive multidisciplinary evaluations. Our observational research is grounded in a multimodal omics and imaging approach, aimed at investigating both local and systemic injuries subsequent to intracranial hemorrhage. This comprehensive strategy is intended to facilitate precise diagnosis, risk stratification, and clinical decision-making, while also shedding light on the pathophysiological mechanisms involved. The primary objectives of this research are to address the following key questions: * \[Question 1\] What are the pathophysiological mechanisms underlying cardiac injury in patients with intracranial hemorrhage? * \[Question 2\] What are the pathophysiological mechanisms responsible for early and delayed brain injuries following intracranial hemorrhage?\"

Efficacy of Daily IV Administration of Dornase Alfa Up to 14 Days Post Subarachnoid Hemorrhage on Functional Independence At 6 Months

Subarachnoid hemorrhage due to aneurysm rupture (SAH) results in high mortality, while survivors frequently suffer reduced quality of life and even loss of autonomy, particularly in the active population. A significant proportion of this morbidity and mortality is linked to the occurrence of delayed cerebral ischemia (DCI), defined as a new focal neurological deficit or reduced level of consciousness unrelated to the treatment of the aneurysm or a concomitant condition. DCI mainly occurs between days 4 and 14 after SAH, with an estimated incidence of 30%, and is significantly associated with an unfavorable functional prognosis at 3 months. Currently, the only treatment for post-SAH DCI is to prevent or reverse the onset of vasospasm, with limited efficacy, for example through nimodipine administration or hemodynamic optimization. However, according to existing data, vasospasm is not the only cause of DCI, as it may occur elsewhere than in the arterial territory affected by vasospasm, or even in the absence of any vasospasm at all. Recent reviews of the literature highlight the role of microvascular thrombo-inflammation in the pathophysiology of DCI. This phenomenon begins as soon as SAH occurs, with the appearance of multiple microvascular obstructions responsible for ischemia of downstream territories and loss of distal autoregulatory capacity. Among the effectors of thrombo-inflammation, the NETose phenomenon (production of NETs - Neutrophil Extracellular Traps or extracellular DNA network) has recently been associated with the onset of DCI. Indeed, the concentration of NETs increases in the cerebrospinal fluid (CSF) and blood of SAH patients, and correlates with the severity of the hemorrhage. Furthermore, intravenous or intraperitoneal administration of DNAse in an animal model of SAH has been shown to reduce NET concentration and improve functional prognosis by acting directly on cerebral perfusion through the reduction of micro-thrombosis. In humans, recombinant DNAse (dornase alfa, Pulmozyme®) has marketing authorization for inhaled administration in cystic fibrosis. The toxicology report accompanying the marketing authorization demonstrates the absence of serious side effects following administration of high IV doses of Pulmozyme® in monkeys and rats. Other studies evaluating IV administration of bovine DNAse at high doses report no complications. In 1999, a study was published evaluating intravenous (IV) Pulmozyme® in lupus patients, reporting no serious adverse events (SAEs) among the 14 patients receiving the treatment. We are currently conducting a clinical trial of the same molecule in IV administration in patients treated with mechanical thrombectomy and IV thrombolysis for ischemic stroke (NCT04785066). This study is the first randomized clinical trial to target NETs as effectors of the thrombo-inflammation responsible for post-HSA DCI.

Improving Outcome in Subarachnoid Hemorrhage wIth Nadroparine

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) was long thought to be caused by subarachnoid blood-induced vasospasm. Experimental and clinical evidence suggest activation of several pathophysiological pathways, affecting the cerebral microcirculation. Recently, lower in-hospital mortality and less non-home discharge was reported in patients treated with therapeutic low-molecular weight heparin (LMWH), compared to patients with standard, prophylactic LMWH, pointing towards a potential benefit of higher doses of LMWH in the acute course after aSAH. Treatment with therapeutic LMWH might improve clinical outcome in endovascularly treated aSAH patients. The primary objective is to evaluate whether aSAH patients treated with therapeutic LMWH have a lower 30-day mortality rate compared to patients treated with prophylactic LMWH. Secondary objectives are to evaluate whether there are significant differences between patients treated with therapeutic and prophylactic LMWH in development of DCI, (hemorrhagic) complications during admission, hydrocephalus, non-home discharge location, quality of life, clinical outcome and cognitive functioning at three and six months, total health care costs. A single center, prospective, phase II randomized clinical trial in aneurysmal SAH patients ≥18 years old, in whom the causative aneurysm is treated with endovascular coiling less than 72 hours after initial SAH. Patients are randomized into 2 groups: (1) Therapeutic dose LMWH group: the standard prophylactic dose, administered upon hospital admission, will be replaced by nadroparin s.c. twice daily 5700 IE anti-Xa, starting within 24 hours after coiling and continued until 21 days after ictus of initial SAH. After 21 days, patients will continue with standard care prophylactic dose until discharge or when mobilized for more than 6 hours per day; (2) Control group: standard of care treatment with prophylactic dose of LMWH; nadroparin, s.c. once daily 2850 AxaIU until discharge or when mobilized for at least 6 hours a day. Primary outcome: 30-days' mortality. Secondary outcome: DCI, venous thrombo-embolic complications, occurrence of major and non-major bleeding, hemorrhagic complications after external ventricular/lumbar drain (EVD/ELD) placement and lumbar puncture (LP), other SAH-related complications, shunt-dependent hydrocephalus, discharge location, quality of life, total health care costs, cognitive functioning, clinical outcome.

CT Perfusion Imaging to Predict Vasospasm in Subarachnoid Hemorrhage

Patients with brain hemorrhage resulting from a ruptured aneurysm (SAH) are at risk of developing a condition called vasospasm, one or two weeks after their hemorrhage. This is a major cause of stroke and death following SAH. A special type of CT scan, called CT perfusion, analyzes regional blood flow in the brain. We hypothesize that CT perfusion scans performed on admission and day 6 post-hemorrhage will enable us to predict which patients will go on to develop vasospasm.

Minocycline for Aneurysmal Subarachnoid Hemorrhage (MASH)

Previous work has demonstrated patients presenting with ruptured aneurysms that develop radiographic and clinical vasospasm have a higher permeability of the blood brain membrane. Matrix metalloproteinase 9 (MMP9) has been studied and recently implicated in both the pathogenesis of the blood brain barrier breakdown and vasogenic edema of ischemia strokes, and is suggested to be an accurate biomarker to predict the onset of cerebral vasospasm after subarachnoid hemorrhage. The therapeutic benefit of minocycline, an MMP9 inhibitor, has been investigated in ischemic stroke population, however its role in the treatment of cerebral vasospasm from ruptured aneurysms remains unknown. Our project has two main goals: to further confirm MMP9 has a reliable biomarker for the onset of cerebral vasospasm, and secondarily to investigate any possible therapeutic benefit that minocycline has in the vasospasm population. Vasospasm continues to be one of the major contributors of morbidity and mortality in the ruptured aneurysm population, and close monitoring of the neurologic exam during the 'vasospasm window' usually requires two weeks in the intensive care unit in most academic settings. As such, if we are better able to predict which patients are at risk of developing vasospasm based on MMP9 levels, we will be better able to anticipate the need for intervention and therefore mitigate the risk of vasospasm induced ischemic strokes, ultimately resulting in better outcomes in the ruptured aneurysm population. Further, if we are able to identify minocycline as a therapeutic agent to deter, or lessen the severity of vasospasm, we can possibly improve neurologic outcomes, decrease hospital stays, ultimately providing an improved and more cost-effective treatment strategy to our patients.