Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Acute Ischemic Cerebral and Renal Events After Transcatheter Aortic Valve Implantation

NCT ID: NCT05145283

Last Updated: 2025-03-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-16
• Study Completion Date: 2025-12-31

Brief Summary

The aim of this trial is to assess the safety and efficacy of conestat alfa (Ruconest®, Pharming Technologies B.V.) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic aortic stenosis (AS) compared to placebo.

Detailed Description

Severe aortic stenosis (AS) is a frequent 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 implantation (TAVI) has 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, embolic events originating from the calcified valve and leading to ischemic stroke 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) such as the Sentinel® CEPD (Boston Scientific) 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 activation and the complement system and attraction of neutrophils to the site of injury. In this regard, recombinant human C1 esterase inhibitor (rhC1INH, conestat alfa), 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 successfully been investigated in a pilot study of acute kidney injury following the administration of contrast media. The aim of the current trial is to assess the safety and efficacy of conestat alfa (Ruconest®, Pharming Technologies B.V.) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic AS compared to placebo.

Conditions

Acute Ischemic Stroke; Acute Renal Injury

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Conestat alfa (Ruconest®) intervention group

The intervention group will receive conestat alfa (Ruconest®) as a 10-minute slow intravenous injection (up to 56 ml) once during the TAVI procedure followed by a second administration (up to 28 ml) again three hours later. The first administration will include a dosage of 100 U/kg (maximum 8400 U) conestat alfa. The dosing of the second administration will be 50 U/kg (maximum 4200 U).

Group Type: ACTIVE_COMPARATOR

Conestat alfa (Ruconest®)

Intervention Type: DRUG

In the current study, participants will receive two intravenous injections of conestat alfa (immediately during the TAVI procedure and again 3h later) at a dose of 100 U/kg (first dose) and of 50 U/kg (subsequent dose), for patients less than 84 kg; two intravenous injections (immediately during the TAVI procedure and again 4h later) of conestat at a dose of 8400 U (4 vials, first dose) and of 4200 U (2 vials, subsequent dose) for patients of 84 kg body weight or greater. The chosen regimen including repeated administration should increase and maintain serum C1INH levels above twice the serum concentration for six to eight hours in the majority of patients. The timeframe of therapeutic concentrations will cover the period of the TAVI procedure itself and the immediate postprocedural period during which reperfusion and additional ischemic events related to global hypoperfusion may occur.

saline injection placebo group

Subjects randomized into the placebo group will receive an intravenous normal saline injection with corresponding volume over 10 minutes during the TAVI procedure and three hours later after the first administration.

Group Type: PLACEBO_COMPARATOR

NaCl 0.9%)

Intervention Type: DRUG

Normal saline (NaCl 0.9%) will serve as placebo treatment. The respective amount of saline (according to patient weight matching the volume of conestat alfa that would have been used for this patient) will be withdrawn in an opaque syringe for slow IV injection.

Interventions

Conestat alfa (Ruconest®)

In the current study, participants will receive two intravenous injections of conestat alfa (immediately during the TAVI procedure and again 3h later) at a dose of 100 U/kg (first dose) and of 50 U/kg (subsequent dose), for patients less than 84 kg; two intravenous injections (immediately during the TAVI procedure and again 4h later) of conestat at a dose of 8400 U (4 vials, first dose) and of 4200 U (2 vials, subsequent dose) for patients of 84 kg body weight or greater. The chosen regimen including repeated administration should increase and maintain serum C1INH levels above twice the serum concentration for six to eight hours in the majority of patients. The timeframe of therapeutic concentrations will cover the period of the TAVI procedure itself and the immediate postprocedural period during which reperfusion and additional ischemic events related to global hypoperfusion may occur.

Intervention Type: DRUG

NaCl 0.9%)

Normal saline (NaCl 0.9%) will serve as placebo treatment. The respective amount of saline (according to patient weight matching the volume of conestat alfa that would have been used for this patient) will be withdrawn in an opaque syringe for slow IV injection.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Informed consent as documented by signature
• Severe AS and scheduled for transfemoral TAVI

Exclusion Criteria

• Contraindications to the class of drugs under study (C1INH), e.g., known hypersensitivity or allergy to class of drugs or the investigational product
• History of allergy to rabbits (as rhC1INH is derived from the breast milk of transgenic rabbits)
• Women who are pregnant or breast feeding
• Hemodynamic instability requiring emergency TAVI
• Valve-in-valve procedure
• Other access route than transfemoral
• Non-cardiac co-morbidity with expected survival <6 months
• Ischemic or hemorrhagic stroke within 30 days before TAVI
• Dialysis or estimated glomerular filtration rate (eGFR) <20 ml/min/1.73m2
• Contraindication for MRI such as a permanent non-MRI compatible pacemaker or severe claustrophobia
• Liver cirrhosis (any Child-Pugh score)
• Incapacity or inability to provide informed consent
• Participation in another study with investigational drug or medical device within the 30 days preceding and during the present study
• Previous enrolment into the current study
• Any uncontrolled or significant concurrent illness that would put the patient at a greater risk or limit compliance with the study requirements at the discretion of the investigator

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swiss National Science Foundation

OTHER

Sponsor Role: collaborator

Pharming Technologies B.V.

INDUSTRY

Sponsor Role: collaborator

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Osthoff, Prof. Dr. med.

Role: PRINCIPAL_INVESTIGATOR

University Hospital Basel, Division of Internal Medicine

Raban Jeger, Prof. Dr. med.

Role: PRINCIPAL_INVESTIGATOR

Stadtspital Triemli Zürich, Division of Cardiology

Locations

University Hospital Basel, Division of Internal Medicine

Basel, , Switzerland

Site Status: RECRUITING

Stadtspital Triemli Zürich, Division of Cardiology

Zurich, , Switzerland

Site Status: RECRUITING

Countries

Switzerland

Central Contacts

Michael Osthoff, Prof. Dr. med.

Role: CONTACT

michael.osthoff@usb.ch

+41 61 328 54 20

Stephan Moser, Dr. med.

Role: CONTACT

stephan.moser@usb.ch

+41 61 265 25 25

Facility Contacts

Michael Osthoff, Prof Dr. med.

Role: primary

michael.osthoff@usb.ch

+41 61 328 54 20

Stephan Moser, Dr.med.

Role: backup

stephan.moser@usb.ch

+41 61 265 25 25

Raban Jeger, Prof. Dr. med.

Role: primary

raban.jeger@stadtspital.ch

+41 44 416 34 11

Other Identifiers

2021-02025; me19Osthoff

Identifier Type: -

Identifier Source: org_study_id