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

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University Hospital Basel

Status and phase

Enrolling
Phase 2

Conditions

Acute Renal Injury
Acute Ischemic Stroke

Treatments

Drug: Conestat alfa (Ruconest®)
Drug: NaCl 0.9%)

Study type

Interventional

Funder types

Other
Industry

Identifiers

NCT05145283
2021-02025 me19Osthoff;

Details and patient eligibility

About

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.

Full 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.

Enrollment

250 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Prevention

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Double Blind

250 participants in 2 patient groups, including a placebo group

Conestat alfa (Ruconest®) intervention group
Active Comparator group
Description:
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).
Treatment:
Drug: Conestat alfa (Ruconest®)
saline injection placebo group
Placebo Comparator group
Description:
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.
Treatment:
Drug: NaCl 0.9%)

Trial contacts and locations

2

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Central trial contact

Michael Osthoff, Prof. Dr. med.; Stephan Moser, Dr. med.

Data sourced from clinicaltrials.gov

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