Project

Back to overview

Recombinant human C1 esterase inhibitor in the prevention of acute ischemic cerebral and renal event after transcatheter aortic valve implantation

English title Recombinant human C1 esterase inhibitor in the prevention of acute ischemic cerebral and renal event after transcatheter aortic valve implantation
Applicant Osthoff Michael
Number 197880
Funding scheme Project funding (Div. I-III)
Research institution Kantonsspital Basel Universitätskliniken Medizinische Klinik 1
Institution of higher education University of Basel - BS
Main discipline Clinical Cardiovascular Research
Start/End 01.01.2021 - 31.12.2023
Approved amount 650'988.00
Show all

All Disciplines (4)

Discipline
Clinical Cardiovascular Research
Neurology, Psychiatry
Internal Medicine
Clinical Immunology and Immunopathology

Keywords (6)

Ischemic stroke; Renal failure; Transcatheter aortic valve implantation; Aortic stenosis; C1 esterase inhibitor; complement system

Lay Summary (German)

Lead
Der kathetergestützte Ersatz einer stark verengten Aortenklappe (sog. TAVI) hat die Behandlung revolutioniert, so dass eine Operation häufig nicht mehr notwendig ist. Als Komplikationen können Durchblutungsstörungen im Gehirn und den Nieren auftreten, die Entzündungsreaktionen auslösen und Gewebeschäden verursachen können. Die PAIR-TAVI Studie untersucht die Wirkung von Conestat alfa, einem entzündungshemmenden Medikament, bei Patienten, die sich einer TAVI unterziehen.
Lay summary

Conestat alfa ist ein künstlich hergestelltes Körpereiweiss, das die durch Durchblutungsstörungen in Gehirn und Niere ausgelösten Entzündungsreaktionen blockiert. Im Tiermodell konnte gezeigt werden, dass durch Conestat alfa Gewebeschäden vermindert werden können. Zudem erzielte eine erste Studie am Menschen vielversprechende Ergebnisse. Die PAIR-TAVI Studie untersucht, ob die Verabreichung von Conestat alfa im Rahmen einer TAVI, das Ausmass des Gewebeschadens in Gehirn und Niere vermindern kann.

Die Studie wird am Universitätsspital Basel durchgeführt. Ca. 120 Patienten, die sich einer TAVI unterziehen, werden zufällig entweder mit Conestat alfa oder einem Scheinpräparat behandelt. Zudem kommt nach Möglichkeit ein Schutzsystem zum Einsatz, welches die Verschleppung von Gerinnseln ins Gehirn verhindern soll. Wirksamkeit (Gewebeschaden in Gehirn und Niere, Auswirkung auf die Hirnleistung) und Verträglichkeit werden über 3 Monate u.a. mittels Magnetresonanztomographie untersucht.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Sollte Conestat alfa erfolgreich das Auftreten von Gewebeschäden bei Patienten nach TAVI vermindern, würde dies wesentlich zur Sicherheit dieses Verfahrens beitragen. Zudem würden sich neue, innovative Behandlungsperspektiven bei anderen Durchblutungsstörungen, wie z.B. dem Schlaganfall, eröffnen.

Direct link to Lay Summary Last update: 22.10.2020

Responsible applicant and co-applicants

Employees

Name Institute

Project partner

Associated projects

Number Title Start Funding scheme
198403 Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. 01.08.2020 NRP 78 Covid-19
192453 Atrial fibrillation before and after patent foramen ovale closure (ALFA ROMEO) study 01.07.2020 Project funding (Div. I-III)

Abstract

Background: Severe aortic stenosis (AS) is the most common valvular heart disease in the elderly with a prevalence of 4 to 10% and a mean survival of only 0.5 to 5 years if left untreated. Transcatheter aortic valve implantations (TAVI) have evolved as standard of care for high-, intermediate and potentially even low surgical risk candidates due to a lower perioperative risk compared to surgical aortic valve replacement (SAVR). Despite its relative safety compared to SAVR, cerebral embolic events including cerebrovascular events and acute renal injury are major complications following TAVI in the acute and subacute period, and are associated with increased morbidity including cognitive decline and mortality. While cerebral embolic protection devices (CEPD) were designed to reduce the burden of cerebral embolic events, their impact on clinical events has yet to be determined, and other prophylactic options are currently not available. Ischemia/reperfusion injury (IRI) is a key pathophysiological mechanism involved in cerebral and renal embolic events after TAVI resulting in activation of endothelial cells, the contact and the complement system and attraction of neutrophils to the site of injury. In this regard, recombinant human C1 esterase inhibitor (rhC1INH), a potent inhibitor of the complement and the contact system has been shown to reduce the size of cerebral ischemic damage and of renal injury in experimental IRI models, and has already been investigated in a pilot study of acute kidney injury following the administration of contrast media.Aims: To assess the safety and effect of rhC1INH (conestat alfa, Ruconest®) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic AS compared to placebo. Hypothesis: Administration of rhC1INH before and three hours after the TAVI procedure is safe and associated with a reduced cerebral ischemic lesion burden and less renal injury compared to placebo.Methodology: The PAIR-TAVI study is a single-center, randomized, double-blind, placebo-controlled investigational study. The primary endpoint will be the total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI) on day 2 (+/-1 day) after transfemoral TAVI. Secondary endpoints will include the occurrence of acute kidney injury, and neurological and cognitive outcome up to 90 days. All clinical endpoint-qualifying events will be assessed by an independent critical event committee. Consecutive patients scheduled for elective transfemoral TAVI will be randomized in a 1:1 ratio to receive rhC1INH before and 3 hours after TAVI or placebo, while being stratified to the use of a CEPD. 104 evaluable patients will ensure a power of 80% to detect a 50% relative reduction in the total new cerebral lesion volume as significant deviation from the null-hypothesis. Assuming a 15% drop-out rate, we will include 122 patients. Potential significance: The current study proposes an innovative approach to renal and neuroprotection in patients undergoing TAVI by investigating the prophylactic administration of a multiple-action multiple-target inhibitor. If rhC1INH proves to decrease IRI in vulnerable organs such as the brain or the kidneys following transfemoral TAVI, the attenuation of some the most feared complications of TAVI might offer new perspectives in the treatment of patients with severe symptomatic AS but also for other indications such as ischemic stroke. Collaborators and setting: Cardiology and Internal Medicine Unit of the University Hospital Basel. The Neurology, Radiology and Clinical Trial Unit of the University Hospital Basel will provide scientific, logistic and statistical support for the study, respectively.
-